EP2718290B1 - Compositions and methods for modulating a kinase - Google Patents

Compositions and methods for modulating a kinase Download PDF

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Publication number
EP2718290B1
EP2718290B1 EP12780531.5A EP12780531A EP2718290B1 EP 2718290 B1 EP2718290 B1 EP 2718290B1 EP 12780531 A EP12780531 A EP 12780531A EP 2718290 B1 EP2718290 B1 EP 2718290B1
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compound
branched
linear
cancer
unsubstituted
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German (de)
English (en)
French (fr)
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EP2718290A2 (en
Inventor
Oren M. Becker
Itai BLOCH
Efrat Ben-Zeev
Alina Shitrit
Avihai Yacovan
Sharon Gazal
Vered Behar
Alexander KONSON
Nili Schutz
Sima Mirilashvili
Gali Golan
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Clevexel Pharma
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Clevexel Pharma
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Priority to HRP20160879TT priority Critical patent/HRP20160879T1/hr
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Definitions

  • Signal transduction is any process by which a cell converts one kind of signal or stimulus into another.
  • Signal transduction processes often involve a sequence of biochemical reactions inside the cell, which are carried out by enzymes and linked through second messengers.
  • an increasing number of enzymes and other molecules become engaged in the events that proceed from the initial stimulus.
  • the chain of steps is referred to as a “signaling cascade” or a "second messenger pathway” and often results in a small stimulus eliciting a large response.
  • One class of molecules involved in signal transduction is the kinase family of enzymes.
  • the largest group of kinases is protein kinases, which act on and modify the activity of specific proteins. These are used extensively to transmit signals and control complex processes in cells.
  • Protein kinases are a large class of enzymes which catalyze the transfer of the ⁇ -phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: growth, proliferation, differentiation, survival, adhesion, migration. There are estimated to be about 2,000 distinct protein kinases in the human body, and although each of these phosphorylate particular protein/peptide substrates, they all bind the same second substrate, ATP, in a highly conserved pocket. Protein phosphatases catalyze the transfer of phosphate in the opposite direction.
  • a tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a tyrosine residue in a protein. Phosphorylation of proteins by kinases is an important mechanism in signal transduction for regulation of enzyme activity.
  • the tyrosine kinases are divided into two groups; those that are cytoplasmic proteins and the transmembrane receptor-linked kinases. In humans, there are 32 cytoplasmic protein tyrosine kinases and 58 receptor-linked protein-tyrosine kinases.
  • the hormones and growth factors that act on cell surface tyrosine kinase-linked receptors are generally growth-promoting and function to stimulate cell division (e.g., insulin, insulin-like growth factor 1, epidermal growth factor).
  • Inhibitors of various known protein kinases or protein phosphatases have a variety of therapeutic applications.
  • One promising potential therapeutic use for protein kinase or protein phosphatase inhibitors is as anti-cancer agents.
  • About 50% of the known oncogene products are protein tyrosine kinases (PTKs) and their kinase activity has been shown to lead to cell transformation.
  • PTKs protein tyrosine kinases
  • kinases are involved in the regulation of a wide variety of normal cellular signal transduction pathways (e.g., cell growth, proliferation, differentiation, survival, adhesion, migration, etc.), kinases are thought to play a role in a variety of diseases and disorders. Thus, modulation of kinase signaling cascades may be an important way to treat or prevent such diseases and disorders.
  • Compounds of the invention may be useful for modulating one or more components involved in a normal cellular signal transduction pathway (e.g., cell growth, proliferation, differentiation, survival, adhesion, migration, etc.), or one involved in a disease or disorder.
  • diseases and disorders include, without limitation, cell proliferative disorders including, cancers; inflammatory disorders; immune disorders including, autoimmune disorders, immune system dysfunction, and transplant rejection, and dry eye disease (xerophthalmia).
  • compounds of the invention may be useful as modulators (e.g ., inhibitors) of a tyrosine kinase e.g., one or more components of a kinase signaling cascade, such as JAK, SYK, and/or BTK.
  • Compounds of the invention may also be useful in treating diseases and disorders that are modulated by a signal transduction pathway, such as a pathway modulated by a spleen tyrosine kinase (SYK) e.g., the BCR signaling pathway.
  • a signal transduction pathway such as a pathway modulated by a spleen tyrosine kinase (SYK) e.g., the BCR signaling pathway.
  • SYK spleen tyrosine kinase
  • compounds of the invention may be useful in treating diseases and disorders that are modulated by SYK inhibition.
  • Compounds of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signal transduction pathway that does not include a spleen tyrosine kinase.
  • Compounds of the invention may also be useful in treating diseases and disorders that are modulated by a signal transduction pathway, such as a pathway modulated by a Bruton's tyrosine kinase (BTK).
  • a signal transduction pathway such as a pathway modulated by a Bruton's tyrosine kinase (BTK).
  • BTK Bruton's tyrosine kinase
  • compounds of the invention may be useful in treating diseases and disorders that are modulated by BTK inhibition.
  • Compounds of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signal transduction pathway that does not include a Bruton's tyrosine kinase.
  • Compounds of the invention may also be useful in treating diseases and disorders that are modulated by a signal transduction pathway, such as a pathway modulated by a Janus kinase (JAK).
  • a signal transduction pathway such as a pathway modulated by a Janus kinase (JAK).
  • JAK inhibition e.g ., JAK3
  • Compounds of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signal transduction pathway that does not include a Janus kinase.
  • the compounds of the invention may be useful as anti-proliferative agents, for treating mammals, such as for treating humans and animals.
  • Compounds of the invention may be used without limitation, for example, as anti-cancer, anti-inflammatory and/or immunosuppressive agents.
  • the invention includes a compound of Formula I: or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein R 1 , R 2 and R 3 are as described herein, for use as pharmaceutical agent.
  • a compound of the invention is used as an anti-proliferative agent, for treating humans and/or animals, such as for treating humans and/or other mammals.
  • a compound of the invention may be used without limitation, for example, as anti-cancer, anti-inflammatory and/or immunosuppressive agents.
  • a compound of the invention may be used for cell proliferation-related disorders and autoimmune disorders.
  • a compound of the invention may be used for dry eye disease.
  • a compound of the invention may be used to treat or prevent a cell proliferation disorder in a subject.
  • the cell proliferation disorder is pre-cancer or cancer.
  • the cell proliferation disorder is a hyperproliferative disorder.
  • prevention or treatment of the cell proliferation disorder, cancer or hyperproliferative disorder occurs through the inhibition of a tyrosine kinase, such as JAK(JAK3), SYK, or BTK.
  • the subject is a mammal, e.g., a human.
  • compounds of the invention are used alone for preventing or treating cancer and/or cell proliferation disorder.
  • the compounds of the invention are used in combination with other therapeutic agents (e.g., a cancer metabolism modulators or a cytotoxic agent) and/or non-drug therapies (e.g., surgery, immunotherapy or radiation treatment).
  • the additional therapy is conducted substantially simultaneously or concurrently with the administration of the pharmaceutical composition.
  • the administration of the pharmaceutical composition is conducted prior to the additional therapy of the combination therapy.
  • the administration of the pharmaceutical composition is conducted subsequent to the additional therapy.
  • the pharmaceutical composition is administered chronically (e.g ., as part of a maintenance therapy).
  • the cancer and/or cell proliferation disorder is a cell proliferative disorder of the hematologic system (e.g ., leukemia or lymphoma).
  • the cancer of the hematologic system is leukemia.
  • the leukemia is myelofibrosis.
  • the leukemia is acute myelogenous leukemia (AML).
  • the cell proliferation disorder is selected from polycythaemia vera (erythremia) and essential thrombocythemia.
  • the cancer and/or cell proliferation disorder is a cell proliferative disorder of the lung (e.g., lung cancer).
  • the cancer and/or cell proliferation disorder is a cell proliferative disorder of the colon (e.g., colon cancer). In some embodiments, the cancer and/or cell proliferation disorder is a cell proliferative disorder of the pancreas ( e.g ., pancreatic cancer). In some embodiments, the cancer and/or cell proliferation disorder is a cell proliferative disorder of the prostate ( e.g ., prostate cancer). In some embodiments, the cancer and/or cell proliferation disorder is a cell proliferative disorder of the skin ( e.g., a skin cancer). In some embodiments, the cancer and/or cell proliferation disorder is a cell proliferative disorder of the ovary ( e.g ., ovarian cancer). In some embodiments, the cancer and/or cell proliferation disorder is a cell proliferative disorder of the breast ( e.g ., breast cancer).
  • compounds of the invention are used for regulating immune system activity.
  • modulating immune system activity includes modulating autoimmune diseases such as transplant rejection (e.g ., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, psoriatic arthritis, and amyotrophic lateral sclerosis.
  • the autoimmune disease is selected from psoriasis, rheumatoid arthritis, and psoriatic arthritis.
  • the invention includes use of a compound of the invention in the manufacture of a medicament to regulate immune system activity. In certain embodiments, regulation of the immune system occurs through the inhibition of lymphocyte proliferation.
  • regulation of the immune system occurs through the inhibition of lymphocyte activation.
  • T-cell proliferation and/or activation is inhibited.
  • B-cell proliferation and/or activation is inhibited.
  • the subject is a mammal, e.g., a human.
  • the invention includes use of a compound of the invention in the manufacture of a medicament to treat or prevent an inflammatory disorder or disease.
  • the inflammatory disease is selected from inflammatory bowel disease and ankylosing spondylitis.
  • the inflammatory bowel disease is selected from ulcerative colitis and Crohn's disease.
  • the invention includes use of a compound of the invention in the manufacture of a medicament to treat or prevent dry eye disease.
  • administration of a compound of the invention is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • a compound of the invention is administered with a pharmaceutically acceptable carrier.
  • a compound of the invention is administered before the onset of immune system irregularity.
  • a compound of the invention is administered after the onset of immune system irregularity.
  • the application is also directed to certain polymorphs of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide and of the hydrochloric acid salt of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide and pharmaceutical compositions thereof.
  • the compound 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide or a pharmaceutically acceptable salt thereof or a polymorph of the compound or salt is useful for modulating one or more components involved in a normal signal transduction pathway (e.g., cell growth, proliferation, differentiation, survival, adhesion, migration, etc.) More specifically, this compound modulates one or more components of a kinase signaling pathway, such as a pathway modulated by Janus kinase (JAK e.g., JAK3), spleen tyrosine kinase (SYK) and/or Bruton's tyrosine kinase (BTK).
  • a kinase signaling pathway such as a pathway modulated by Janus kinase (JAK e.g., JAK3), spleen tyros
  • This compound is useful in treating diseases and disorders that are modulated by a signal transduction pathway.
  • 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt is useful in the treatment of cell proliferative disorders, including cancers; inflammatory disorders; immune disorders, including automimmune disorders, immune system dysfunction, and transplant rejection; and dry eye disease.
  • 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide and the hydrochloride salt of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide can each exist as a novel crystalline form.
  • the polymorphs of the present invention exhibit properties that render them superior to previously known compounds and pharmaceutically acceptable salts thereof.
  • kinases are involved in the regulation of a wide variety of normal cellular signal transduction pathways (e.g., cell growth, proliferation, differentiation, survival, adhesion, migration, etc.), kinases are thought to play a role in a variety of diseases and disorders.
  • modulation of kinase signaling cascades may be an important way to treat or prevent such diseases and disorders.
  • diseases and disorders include, for example, cell proliferative disorders including, cancers; inflammatory disorders; immune disorders including autoimmune disorders, immune system dysfunction, and transplant rejection, and dry eye disease (xerophthalmia).
  • a compound of the invention may be useful for modulating one or more components involved in a signal transduction pathway to prevent or to treat a disease or disorder in which the pathway plays a role, such as a pathway modulated by a tyrosine kinase e.g., JAK, SYK, and/or BTK.
  • a compound of the invention may be useful for treating such diseases and disorders including, without limitation, cell proliferative disorders including, cancers; inflammatory disorders, immune disorders including, autoimmune disorders, immune system dysfunction, and transplant rejection, and dry eye disease (xerophthalmia).
  • a compound of the invention may be useful for modulating one or more components involved in a signal transduction pathway to prevent or to treat a disease or disorder in which the pathway plays a role, such as a pathway modulated by a Janus kinase (JAK).
  • JAK Janus kinase
  • the Janus kinases are a family of intracellular non-receptor tyrosine kinases consisting of JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2).
  • the JAKs play a crucial role in cytokine signaling.
  • the downstream substrates of the JAK family of kinases include the signal tranducer activator of transcription (STAT) proteins.
  • JAK/STAT signaling has been implicated in the mediation of many abnormal immune responses such as allergies, asthma, autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as in solid and hematologic malignancies such as leukemia and lymphomas.
  • autoimmune diseases such as transplant (allograft) rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis
  • solid and hematologic malignancies such as leukemia and lymphomas.
  • JAK3 is a member of the Janus family of protein kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoietic cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. JAK3 is involved in signal transduction by noncovalent association with receptors that employ the common gamma chain ( ⁇ C) of the type I cytokine receptor family (e.g. IL-2R, IL-4R, IL-7R, IL-9R, IL-15R, and IL-21R).
  • ⁇ C common gamma chain
  • JAK3 is associated with a variety of human cancers. Individuals with Down syndrome (DS) are predisposed to develop acute megakaryoblastic leukemia (AMKL). The subsequent development of leukemia in DS is often preceded earlier on in life by a transient myeloproliferative disorder (TMD). Acquired mutations in JAK3 have been reported in both DS patients with TMD, and non-DS patients with AMKL ( Walters DK, et al., 2006. Cancer Cell. 10:65-75 , De Vita S., et al., 2007. Br. J. Haematol. 137:337-341 ).
  • JAK3 affects its pseudokinase domain and renders the kinase constitutively active.
  • a point mutation in JAK3 affects its pseudokinase domain and renders the kinase constitutively active.
  • Modulation or inhibition via this mechanism therefore, can prove effective for the treatment of immune proliferative disorders, such as autoimmune diseases (e.g., rheumatoid arthritis) or different forms of leukemia.
  • modulators of signal transduction pathways such as inhibitors of JAK3.
  • a compound of the invention may be useful as modulators (e.g., inhibitors) of one or more components of a JAK kinase signaling cascade, such as JAK3.
  • a compound of the invention may be useful in modulation of more than one component of a JAK kinase signaling cascade.
  • a compound of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signal transduction pathway that does not include a Janus kinase.
  • modulates one or more components of a JAK kinase signaling cascade means that one or more components of the JAK kinase signaling cascade are affected such that the functioning of a cell changes.
  • Components of a protein kinase signaling cascade include any proteins involved directly or indirectly in a JAK kinase signaling pathway including second messengers and upstream and downstream targets.
  • a compound of the invention may be useful for modulating one or more components involved in a signaling pathway to prevent or to treat a disease or disorder in which the pathway plays a role, such as a pathway involving spleen tyrosine kinase (SYK).
  • SYK spleen tyrosine kinase
  • Spleen tyrosine kinase is a member of the SYK family of tyrosine protein kinases, a family of cytoplasmic tyrosine kinases characterized by the presence of two SH2 domains in the amino terminal of a single kinase domain. Homologs of the SYK family of protein kinases have been identified in a number of species, including the human ZAP-70. SYK has been reported to be involved in several cellular signaling events. For example, SYK participates in immunoreceptor signaling, integrin signaling, and G protein-coupled receptor signaling.
  • SYK is known to be expressed in hematopoietic cells as wells as in fibroblasts, epithelial cells, hepatocytes, neuronal cells, endothelial cells and mast cells. SYK is also involved in hematopoietic responses such as proliferation, for example, SYK inhibitors have been suggested as modulators of thrombin-induced ASM cell proliferation, differentiation, and phagocytosis.
  • SYK inhibitors have also been demonstrated to be important in non-hematopoietic cells as well, such as in fibroblasts, epithelial cells, breast tissue, hepatocytes, neuronal cells, and vascular endothelial cells. Accordingly, SYK has been implicated as playing a critical role in endothelial cell functions, including morphogenesis cell growth, migration, and survival, and as contributing to maintaining vascular integrity in vivo. For further review, see Yanagi et al., Biochem. Biophys. Res. Comm. 288:495-498 (2001 ).
  • SYK antisense and specific inhibitors have been shown to have some activity in asthma models and SYK is thought to be a target for the treatment of asthma and other airway diseases, as well as for allergies, inflammation, and autoimmunity. SYK has also been suggested as a target for the development of agonists in cancer therapy, due to its role in cell growth.
  • SYK is essential for B-cell activation through BCR signaling. SYK become activated upon binding to phosphoryated BCR and thus initiates the early signaling events following BCR activation. Mice deficient in SYK exhibit an early block in B-cell development ( Cheng et al. Nature 378:303, 1995 ; Turner et al. Nature 378:298, 1995 ). Therefore inhibition of SYK enzymatic activity in cells is proposed as a treatment for autoimmune disease through its effects on autoantibody production.
  • a compound of the invention may be useful as modulators (e.g., inhibitors) of SYK. Some compounds may be useful in modulation of more than one component of a signaling cascade involving SYK. In one aspect, a compound of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signaling pathway that does not include BTK.
  • a compound of the invention may be useful for modulating one or more components involved in a signaling pathway to prevent or to treat a disease or disorder in which the pathway plays a role, such as a pathway modulated by BTK.
  • BCR B-cell receptor
  • the BCR is a key regulatory point for B-cell activity and aberrant signaling can cause deregulated B-cell proliferation and formation of pathogenic autoantibodies that lead to multiple autoimmune and/or inflammatory diseases.
  • Bruton's Tyrosine Kinase (BTK) is a non-BCR associated kinase that is membrane proximal and immediately downstream from BCR. Lack of BTK has been shown to block BCR signaling and therefore inhibition of BTK could be a useful therapeutic approach to block B-cell mediated disease processes.
  • BTK is a member of the Tec family of tyrosine kinases, and has been shown to be a critical regulator of early B-cell development and mature B-cell activation and survival ( Khan et al. Immunity 1995 3:283 ; Ellmeier et al. J. Exp. Med. 2000 192:1611 ). Mutation of BTK in humans leads to the condition X-linked agammaglobulinemia (XLA) (reviewed in Rosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol. Rev. 2005 203:200 ). These patients are immunocompromised and show impaired maturation of B-cells, decreased immunoglobulin and peripheral B-cell levels, diminished T-cell independent immune responses as well as attenuated calcium mobilization following BCR stimulation.
  • XLA X-linked agammaglobulinemia
  • BTK -deficient mice show marked amelioration of disease progression.
  • Btk-deficient mice are resistant to collagen-induced arthritis ( Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459 ).
  • a selective BTK inhibitor has been demonstrated dose-dependent efficacy in a mouse arthritis model ( Z. Pan et al., Chem. Med Chem. 2007 2:58-61 ).
  • BTK is also expressed by cells other than B-cells that may be involved in disease processes.
  • BTK is expressed by mast cells and BTK -deficient bone marrow derived mast cells demonstrate impaired antigen induced degranulation ( Iwaki et al. J. Biol. Chem. 2005 280:40261 ). This shows BTK could be useful to treat pathological mast cells responses such as allergy and asthma.
  • monocytes from XLA patients, in which BTK activity is absent show decreased TNF alpha production following stimulation ( Horwood et al. J Exp Med 2003 197:1603 ). Therefore TNF alpha mediated inflammation could be modulated by small molecular Btk inhibitors.
  • Btk has been reported to play a role in apoptosis ( Islam and Smith Immunol. Rev. 2000 178:49 ,) and thus BTK inhibitors would be useful for the treatment of certain B-cell lymphomas and leukemias ( Feldhahn et al. J. Exp. Med. 2005 201:1837 ).
  • a compound of the invention may be useful as modulators (e.g., inhibitors) of BTK.
  • a compound of the invention may be useful in modulation of more than one component of a signaling cascade involving BTK.
  • a compound of the invention may also be useful in treating diseases and disorders that are additionally or alternatively, modulated by a signaling pathway that does not include BTK.
  • a compound of the invention is useful as a pharmaceutical agent, for example, as therapeutic agent for treating humans and animals.
  • a compound of the invention may be used without limitation, for example, as anti-cancer, anti-inflammatory, and/or immunosuppressive agents.
  • a compound of the invention may be used for other cell proliferation-related disorders and autoimmune disorders.
  • a compound of the invention may be used to regulate immune system activity in a subject, thereby protecting against or preventing autoimmune disease, e.g., lupus, transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, psoriatic arthritis, and amyotrophic lateral sclerosis, sepsis, T-cell mediated autoimmune diseases such as multiple sclerosis, psoriasis and Sjogren's syndrome, and hypersensitivity reactions.
  • autoimmune disease e.g., lupus, transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, psoriatic arthritis, and amyotrophic lateral sclerosis, sepsis, T-cell mediated autoimmune diseases such as multiple sclerosis, ps
  • a compound of the invention may also be used to protect against or prevent solid and hematologic malignancies, e.g., leukemia and lymphomas.
  • the invention includes a compound of the invention in the manufacture of a medicament to regulate the immune system.
  • a compound of the invention may be used to treat autoimmune disease in a subject.
  • the invention includes use of a compound of the invention in the manufacture of a medicament to protect against or treat solid and hematologic malignancies.
  • a compound of the invention may result in reduction in the severity of symptoms or halt impending progression of the autoimmune disease, or solid or hematologic malignancy in a subject.
  • regulation of the immune system occurs through the inhibition of lymphocyte proliferation. In certain embodiments, regulation of the immune system occurs through the inhibition of lymphocyte activation. For example, T-cell proliferation and/or activation is inhibited. Additionally or alternatively, B-cell proliferation and/or activation is inhibited. In certain embodiments, the subject is a mammal, e.g., a human.
  • a compound of the invention may be involved in modulating a kinase signaling cascade, e.g., a Janus kinase (JAK) inhibitor such as a JAK1, JAK2, JAK3 or TYK2 inhibitor.
  • a kinase signaling cascade e.g., a Janus kinase (JAK) inhibitor such as a JAK1, JAK2, JAK3 or TYK2 inhibitor.
  • a compound of the invention modulates ones or more members of the JAK kinase family (e.g., JAK1, JAK2, JAK3, or TYK2) and is useful for the treatment of immune mediated diseases, e.g., hypersensitivity reactions, transplant rejection (e.g., acute and chronic transplant rejection), allergies, rheumatoid arthritis, psoriatic arthritis, amyotrohopic lateral sclerosis, and malignanices, e.g., leukemia and lymphoma.
  • a compound of the invention used for treating, preventing or ameliorating immune mediated disease is an inhibitor of a tyrosine kinase.
  • a compound of the invention used in the methods of treating, prevention or ameliorating immune mediated disease is an inhibitor of a tyrosine kinease selected from JAK(JAK3), SYK, and BTK.
  • JAK3 kinase binds the common gamma chain of cytokinetic receptors.
  • This common gamma chain which is involved in both ligand binding and signal transduction, is a shared subunit of the multichain receptor for cytokines IL-2, IL-4, IL-7, IL-9, IL- 15 and IL-21.
  • a compound of the invention may be used to regulate, and in particular inhibit, these and other cytokine receptor signaling cascades which utilize the common gamma chain.
  • the invention includes compounds for use for regulating, and in particular inhibiting, signal transduction cascades in which a JAK kinase plays a role, such as signal transduction cascades of cytokine receptors utilizing the common gamma chain, including, but not limited to, the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signal transduction cascades.
  • Compounds of the invention may also be used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular JAK-dependent signal transduction cascade...
  • diseases that are mediated, at least in part, by JAK kinases that can be treated or prevented with compounds of the invention include, but are not limited to, allergies, asthma, autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, psoriatic arthritis, and amyotrophic lateral sclerosis, multiple sclerosis, psoriasis and Sjogren' syndrome, Type II inflammatory disease such as vascular inflammation (including vasculitis, ateritis, atherosclerosis and coronary artery disease), chronic inflammatory diseases such as ankylosing spondylitis (also known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strumpell diseases), diseases of the central nervous system such as stroke, pulmonary diseases such as bronchitis obliterous and primary and primary pulmonary hypertension, delayed or cell-mediated, Type IV hyper
  • a compound of the invention may be involved in modulating a kinase signaling cascade, e.g., a spleen tyrosine kinase (SYK) inhibitor such as a SYK or Zap-70 inhibitor.
  • a kinase signaling cascade e.g., a spleen tyrosine kinase (SYK) inhibitor such as a SYK or Zap-70 inhibitor.
  • SYK spleen tyrosine kinase
  • a compound of the invention modulates ones or more members of the SYK kinase family (e.g., SYK or Zap-70) and is useful for the treatment of immune mediated diseases, e.g., hypersensitivity reactions, transplant rejection (e.g., acute and chronic transplant rejection), allergies, rheumatoid arthritis, psoriatic arthritis, amyotrohopic lateral sclerosis, and malignanices, e.g., leukemia and lymphoma.
  • a compound of the invention is used for treating, preventing or ameliorating immune mediated disease is an inhibitor of a tyrosine kinase.
  • a compound of the invention is used for treating, prevention or ameliorating immune mediated disease is an inhibitor of a tyrosine kinease selected from JAK (JAK3), SYK, and BTK.
  • the Syk family of tyrosine kinases includes e.g., SYK and Zap-70.
  • SYK plays a role in the signaling cascades from a certain cell surface receptors (e.g., CD74, Fc Receptor, and integrins).
  • a compound of the invention may be used to regulate, and in particular inhibit, these and similar receptors.
  • compounds of the invention are used for regulating, and in particular inhibiting, signal transduction cascades in which a SYK kinase plays a role.
  • Compounds fo the invention may also be used to regulate, and in particular inhibit, downstream processes or cellular responses elicited by activation of the particular SYK-dependent signal transduction cascade.
  • Compounds may be used to regulate any signal transduction cascade where SYK kinase is now known or later discovered to play a role.
  • Compounds may also be used in in vitro contexts or in in vivo contexts as a therapeutic approach towards the treatment or prevention of diseases characterized by, caused by or associated with activation of the SYK-dependent signal transduction cascade.
  • diseases that are mediated, at least in part, by SYK kinases include, but are not limited to, allergies, asthma, autoimmune diseases such as transplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid arthritis, psoriatic arthritis, and amyotrophic lateral sclerosis, multiple sclerosis, psoriasis and Sjogren' syndrome, Type II inflammatory disease such as vascular inflammation (including vasculitis, ateritis, atherosclerosis and coronary artery disease), chronic inflammatory diseases such as ankylosing spondylitis (also known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strumpell diseases), diseases of the central nervous system such as stroke, pulmonary diseases such as bronchitis obliterous and primary and primary pulmonary hypertension, delayed or cell-mediated, Type IV
  • lymphocytes e.g., B-cells and T-cells
  • compounds described herein may be used to regulate, and in particular inhibit, lymphocyte proliferation and/or activation (e.g., T-cell proliferation and/or activation and/or B-cell proliferation and/or activation).
  • the invention includes a compound according to Formula I: or a pharmaceutically acceptable salt, solvate or polymorph thereof, wherein:
  • the present invention relates to said compounds for use as pharmaceutical agent.
  • the invention includes a compound of Formula I or a salt, or a solvate thereof, wherein:
  • the invention includes a compound of formula II: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R 2 and R 3 are as described for formula I or further herein; R a1 , R a2 , R a3 , R a4 , and R a5 are each independently selected from the group consisting of:
  • the invention includes a compound of formula III: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a3 , R a4 , R 2 , and R 3 are as described for formula I and II herein.
  • the invention includes a compound of formula IV: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a3 , R 2 and R 3 are as described for formula I and II.
  • the invention includes a compound of formula V: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a4 , R 2 and R 3 are as described for formula I and II.
  • the invention includes a compound of formula VI: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a4 , R b , R 2 and R 3 are as described for formula I and II.
  • the invention includes a compound of formula VII: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a3 , R b , R 2 and R 3 are as described for formula I and II.
  • the invention includes a compound of formula VIII: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R a3 , R d , R 2 and R 3 are as described for formula I and II.
  • the invention includes a compound of formula IX: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein , wherein R 2 and R 3 are as described for formula I and II; R a6 and R a7 are each independently selected from the group consisting of:
  • the invention includes a compound of formula X: or polymorph or a pharmaceutically acceptable salt, solvate, thereof, wherein R a7 , R 2 and R 3 are as described for formula IX and I and further herein.
  • the invention includes a compound of formula XI: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R 2 and R 3 are as described for formula I and further herein; R b1 , R b2 , R b3 , R b4 , and R b5 are each independently selected from hydrogen, halogen, CF 3 , C(O)CH 3 , a linear or branched C 1 -C 6 alkyl, a linear or branched C 2 -C 6 alkenyl, a linear or branched C 2 -C 6 alkynyl, a C 3 -C 8 cycloalkyl, a C 3 -C 8 cycloalkenyl, heterocycloalkyl, an aryl and a heteroaryl; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl or heteroaryl is
  • the invention includes a compound of formula XII: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R b1 , R b2 , R b3 , R b4 , R b5 , R 2 and R 3 are as described for formula XI and I and further herein.
  • the invention includes a compound of formula XIII: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R b1 , R 2 and R 3 are as described for formula I and further herein.
  • the invention includes a compound of formula XIV: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R b2 , R 2 and R 3 are as described for formula XI and I and further herein.
  • the invention includes a compound of formula XV: or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein R b3 , R 2 and R 3 are as described for formula XI and I and further herein.
  • the invention includes a compound of Table A. In one aspect, the invention includes a compound of Table B. In one aspect, the invention includes a compound of Table C.
  • Table A Compound Name Structure 16A 17A 13A 15A 14A 18A 19A 20A 21A 22A 23A 24A 25A 26A 27A 28A 29A 30A 31A 32A 33A 34A 35A 36A 37A 38A
  • Table B Compound Name Structure 7A 12A 8A 5A 10A 9A 3A 2A 4A 11A 39A 40A 41A 42A 43A 44A 45A 46A 47A 48A 49A 50A 51A 52A 53A 54A 55A 56A 57A 58A 59A 60A 61A 62A 63A 64A 6A Table C 1B 2B 3B 4B 5B 6B 7B 8B 9B 10B 11B 12B 13B 14B 15B 16B 17B 18B 19B 20B 21B 22B 23B 24B 25B 26B 27B 28B 29B 30B 31B 32B 33B
  • the invention includes a compound selected from Compound 13A, 14A, 15A, 16A, 17A, and 18A.
  • the invention includes a solvate of a compound of the invention. In one aspect, the invention includes a solvate, wherein the solvate is a hydrate of a compound of the invention. In one aspect, the invention includes an acid addition salt of a compound of the invention e.g., a hydrochloride salt. In one aspect, the invention includes a pharmaceutically acceptable salt of a compound of the invention. In one aspect, the invention includes a pharmaceutical composition comprising a compound of the invention and at least one pharmaceutically acceptable excipient.
  • the invention includes any of the compounds listed in Table C or a salt, or solvate thereof, wherein the compound inhibits a tyrosine kinase by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • a compound of the invention inhibits a tyrosine kinase by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • the invention includes any of the compounds listed in Table C or a salt, or solvate" thereof, wherein the compound inhibits JAK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • JAK is JAK3.
  • a compound of the invention inhibits a JAK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • JAK is JAK3.
  • the invention includes any of the compounds listed in Table C or a salt, or solvate" thereof, wherein the compound inhibits SYK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • a compound of the invention inhibits a SYK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • the invention includes any of the compounds listed in Table C or a salt, or solvate thereof, wherein the compound inhibits BTK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • a compound of the invention inhibits BTK by at least about 10%, by at least about 20%, by at least about 25%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, by at least about 75%, by at least about 80%, by at least about 90%, or by about 95% or more.
  • the compounds of the invention are synthesized using methods known to one skilled in the art.
  • the starting material ethyl 4-acetyl-1H-pyrrole-2-carboxylate may be prepared from the commercially available compound ethyl 1H-pyrrole-2-carboxylate according to the published procedure (See, e.g., Journal of the American Chemical Society, 129(11), 3078-3079; 2007 ; Chemical & Pharmaceutical Bulletin, 44(1), 48-54; 1996 ; Heterocycles, 27(8), 1855-60; 1988 ) using acyl chloride as acylating agent.
  • it may be prepared starting from 4-acetyl-1H-pyrrole-2-carboxylic acid, also a commercially available compound (Scheme 1).
  • the imidazole analog may be prepared starting from commercially available ethyl 1H-imidazole-2-carboxylate (Scheme 2).
  • the next step is protecting the pyrrole or imidazole nitrogen and then acetyl bromination (Scheme 3) according to published procedures (See, e.g., Heterocycles, 55(8), 1475-1486; 2001 ; Journal of Medicinal Chemistry, 33(2), 543-52; 1990 ; Eur. Pat. Appl., 259085, 09 Mar 1988 ).
  • the thioamides derivatives used in Scheme 5 may be prepared using BF 3 -etherate assisted conversion of nitriles into thioamides with Lawesson's reagent (See, e.g., Synthesis, (24), 4012-4018; 2008 ; Farmaco, 54(8), 533-541; 1999 ) (Scheme 6).
  • the obtained intermediate [3] undergoes amidation reactions on both sides, one on the ethyl ester moiety and the second one on the amine obtained after reduction of the nitro group.
  • W is hydroxyl, it may undergo an alkylation reaction.
  • the present invention includes crystalline 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) characterized by X-ray diffraction pattern, methods of making, pharmaceutical compositions comprising this polymorph and methods of treating diseases and disorders that are modulated by a signal transduction pathway.
  • 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt Form I is useful in the treatment of cell proliferative disorders, including cancers; inflammatory disorders; immune disorders, including autoimmune disorders, immune system dysfunction, and transplant rejection; and dry eye disease.
  • the hydrochloride salt may be prepared under a variety of different conditions.
  • the certain polymorph 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt Form I is prepared as follows: the free base 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide is dissolved in toluene (by heating) and HCl in EtOH is added dropwise.
  • 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (compound 8) can be recrystallized in ethanol or methanol to afford N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I).
  • the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) has characteristics combined with inertness toward common excipients used in pharmaceutical formulations that make it highly suitable for pharmaceutical formulation use. Furthermore, 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) exhibits superior solubility.
  • the invention provides a polymorph 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said polymorph is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 10 .
  • DSC Differential Scanning Calorimetry
  • the invention provides a polymorph 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said polymorph characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 .
  • the invention provides polymorph 2-morpholino-N-(3-(4-(5-(pyrrolidine-1 carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 20.0, 18.9, and 9.8 degrees 2 ⁇ .
  • the polymorph is characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 21.4, 20.0, 19.6, 18.9, 18.0, 16.4, 16.0, 13.7, and 9.8 degrees 2 ⁇ .
  • the polymorph is characterized by an X-ray diffraction pattern lacking peaks at about 4.3, 19.2, and 22.1 degrees 2 ⁇ .
  • the invention provides a polymorph, wherein said X-ray diffraction is measured with Copper X-ray source.
  • said X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides a polymorph, wherein said DSC thermogram is measured by a DSC Q2000 V24.4 Build 116.
  • the invention provides a polymorph, wherein the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by a process comprising the steps of: 1) heating 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene, and 2) treating said 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene with hydrochloric acid in ethanol.
  • said treating is with a 1.4 M solution of HCl in ethanol.
  • the invention provides a polymorph, wherein 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by recrystallization of the hydrochloride salt of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is selected from ethanol and methanol.
  • the organic solvent is ethanol.
  • the organic solvent is methanol.
  • the invention provides an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 10 .
  • DSC Differential Scanning Calorimetry
  • the invention provides an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 .
  • the invention provides an active ingredient characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 20.0, 18.9, and 9.8 degrees 2 ⁇ .
  • the active ingredient is characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 21.4, 20.0, 19.6, 18.9, 18.0, 16.4, 16.0, 13.7, and 9.8 degrees 2 ⁇ .
  • the active ingredient is characterized by an X-ray diffraction pattern lacking peaks at about 4.3, 19.2, and 22.1 degrees 2 ⁇ .
  • the invention provides an active ingredient, wherein said X-ray diffraction is measured with Copper X-ray source.
  • said X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides an active ingredient, wherein said DSC thermogram is measured by a DSC Q2000 V24.4 Build 116.
  • the invention provides an active ingredient, wherein the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by a process comprising the steps of: 1) heating 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1 H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene, and 2) treating said 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene with hydrochloric acid in ethanol.
  • said treating is with a 1.4 M solution of HCl in ethanol.
  • the invention provides an active ingredient, wherein 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by recrystallization of the hydrochloride salt of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is selected from ethanol and methanol.
  • the organic solvent is ethanol.
  • the organic solvent is methanol.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 10 , and a pharmaceutically acceptable carrier.
  • DSC Differential Scanning Calorimetry
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 , and a pharmaceutically acceptable carrier.
  • an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X
  • the invention provides a pharmaceutical composition
  • an active ingredient comprising 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 10 , and a pharmaceutically acceptable carrier.
  • DSC Differential Scanning Calorimetry
  • the invention provides a pharmaceutical composition
  • an active ingredient comprising 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 8 , and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition, wherein the active ingredient is characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 20.0, 18.9, and 9.8 degrees 2 ⁇ .
  • the invention provides a pharmaceutical composition, wherein the active ingredient is characterized by an X-ray diffraction pattern including characteristic peaks at about 26.4, 24.1, 22.8, 21.4, 20.0, 19.6, 18.9, 18.0, 16.4, 16.0, 13.7, and 9.8 degrees 2 ⁇ .
  • the active ingredient is characterized by an X-ray diffraction pattern lacking peaks at about 4.3, 19.2, and 22.1 degrees 2 ⁇ .
  • the invention provides a pharmaceutical composition, wherein said X-ray diffraction of the active ingredient is measured with Copper X-ray source.
  • said X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides a pharmaceutical composition, wherein said DSC thermogram of the active ingredient is measured by a DSC Q2000 V24.4 Build 116.
  • a pharmaceutical composition wherein the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by a process comprising the steps of: 1) heating 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene, and 2) treating said 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide in toluene with hydrochloric acid in ethanol.
  • said treating is with a 1.4 M solution of HCl in ethanol.
  • the invention provides a pharmaceutical composition, wherein 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) is obtainable by recrystallization of the hydrochloride salt of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is selected from ethanol and methanol.
  • the organic solvent is ethanol.
  • the organic solvent is methanol.
  • the invention provides a polymorph of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said polymorph is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 18 .
  • DSC Differential Scanning Calorimetry
  • the invention provides a polymorph of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said polymorph characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 .
  • the invention provides a polymorph of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) characterized by an X-ray diffraction pattern including characteristic peaks at about 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the polymorph is characterized by an X-ray diffraction pattern including characteristic peaks at about 18.4, 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the polymorph a polymorph of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) is characterized by an X-ray diffraction pattern including characteristic peaks at about 15.4, 18.4, 19.5, 21.3, 22.7, 24.5, 25.2, and 28.0 degrees 2 ⁇ .
  • the invention provides a polymorph, wherein the X-ray diffraction is measured with Copper X-ray source.
  • the X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides a polymorph wherein, the DSC thermogram is measured by a DSC Q2000 V24.4 Build 116.
  • the invention provides a polymorph of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide, wherein the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) is obtainable by recrystallization of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is ethanol.
  • the invention provides an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 18 .
  • DSC Differential Scanning Calorimetry
  • the invention provides an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 .
  • the invention provides an active ingredient of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) characterized by an X-ray diffraction pattern including characteristic peaks at about 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the active ingredient is characterized by an X-ray diffraction pattern including characteristic peaks at about 18.4, 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the active ingredient is characterized by an X-ray diffraction including characteristic peaks at about 15.4, 18.4, 19.5, 21.3, 22.7, 24.5, 25.2, and 28.0 degrees 2 ⁇ .
  • the invention provides an active ingredient, wherein the X-ray diffraction of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) is measured with Copper X-ray source.
  • said X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides an active ingredient, wherein the DSC thermogram of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) is measured by a DSC Q2000 V24.4 Build 116.
  • the invention provides an active ingredient, 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) that is obtainable by recrystallization of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is ethanol.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 19, and a pharmaceutically acceptable carrier.
  • DSC Differential Scanning Calorimetry
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 , and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide(Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 or a Differential Scanning Calorimetry (DSC) thermogram having a decomposition trace substantially similar to that set forth in Figure 18 , and a pharmaceutically acceptable carrier.
  • DSC Differential Scanning Calorimetry
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient consisting of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide(Form I) represented by the formula: wherein, said active ingredient is characterized by at least one of the following: an X-ray diffraction pattern characterized by an X-ray diffraction peak pattern substantially similar to that set forth in Figure 15 , and a pharmaceutically acceptable carrier.
  • the invention provides a pharmaceutical composition comprising an active ingredient characterized by an X-ray diffraction pattern including characteristic peaks at about 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the pharmaceutical composition comprises an active ingredient characterized by an X-ray diffraction pattern including characteristic peaks at about 18.4, 21.3, 22.7, and 24.5 degrees 2 ⁇ .
  • the pharmaceutical composition comprises an active ingredient characterized by an X-ray diffraction pattern lacking peaks at about 15.4, 18.4, 19.5, 21.3, 22.7, 24.5, 25.2, and 28.0 degrees 2 ⁇ .
  • the invention provides a pharmaceutical composition, wherein the X-ray diffraction of the active ingredient is measured with Copper X-ray source.
  • the X-ray diffraction pattern is measured by a Bruker D8 Advance.
  • the invention provides a pharmaceutical composition, wherein the DSC thermogram of the active ingredient is measured by a DSC Q2000 V24.4 Build 116.
  • the invention provides a pharmaceutical composition, wherein the 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide(Form I) is obtainable by recrystallization of 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide from an organic solvent.
  • the organic solvent is ethanol.
  • the invention provides a pharmaceutical composition, wherein said 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I) is substantially free from impurities.
  • compounds of the invention are used for preventing or treating a cell proliferation-related disorder including, cancer; an inflammatory disorder; an immune disorder including, autoimmune disease, immune system dysfunction, and transplant rejection and/or dry eye disease by administering to a subject in need thereof a pharmaceutical composition that includes a compound of the invention and at least one pharmaceutically acceptable excipient to a subject in need thereof.
  • a pharmaceutical composition that includes a compound of the invention that has more than one stereoisomeric form
  • the pharmaceutical composition may be prepared with a pure or an essentially pure enantiomeric form of the compound, with an enantiopurity of at least 90% enantiomeric excess (EE), at least 95% EE, at least 98% EE, and at least 99% EE.
  • the pharmaceutical composition may be prepared as mixture of enantiomeric forms of the compound (e.g ., as a racemic mixture or as a mixture with a ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).
  • the invention also includes use of a compound of the invention in the manufacture of a medicament to prevent or treat a cell proliferation-related disorder including, a cancer; an inflammatory disorder; an immune disorder including, autoimmune disease, immune system dysfunction, and transplant rejection and/or dry eye disease.
  • the medicament when the medicament includes a compound of the invention that has more than one stereoisomeric form, the medicament may be prepared with a pure or an an essentially pure enantiomeric form of the compound, with an enantiopurity of at least 90% enantiomeric excess (EE), at least 95% EE, more at least 98% EE, and at least 99% EE.
  • the medicament may be prepared as mixture of enantiomeric forms of a compound of the invention (e.g ., as a racemic mixture or as a mixture with a ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).
  • Compounds of the invention are also used in combination with at least one pharmaceutically acceptable excipient for treating or preventing a disease or disorder that is modulated by inhibition of one or more tyrosine kinases (JAK, SYK, and/or BTK),.
  • the pharmaceutical composition includes a compound of the invention that has more than one stereoisomeric form
  • the pharmaceutical composition may be prepared with a pure or an essentially pure enantiomeric form of the compound, with an enantiopurity of at least 90% enantiomeric excess (EE), at least 95% EE, at least 98% EE, and at least 99% EE.
  • the pharmaceutical composition may be prepared as mixture of enantiomeric forms of a compound of the invention (e.g ., as a racemic mixture or as a mixture with a ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).
  • the disease or disorder that is modulated by inhibition of one or more tyrosine kinases is cancer, pre-cancer, or a hyperproliferative disorder.
  • the administration of a compound of the invention is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • a compound of the invention is administered with a pharmaceutically acceptable carrier.
  • Compounds of the invention are also used for regulating immune system activity.
  • Embodiments of the invention also include use of a compound of the invention in the manufacture of a medicament to regulate immune system activity.
  • diseases that may be treated or prevented with the compounds of the invention include, but are not limited to, allergies, asthma, autoimmune diseases such as transplant rejection (e.g., kidney, heart,.
  • rheumatoid arthritis psoriatic arthritis
  • amyotrophic lateral sclerosis multiple sclerosis, psoriasis and Sjogren' syndrome
  • Type II inflammatory disease such as vascular inflammation (including vasculitis, ateritis, atherosclerosis and coronary artery disease), chronic inflammatory diseases such as ankylosing spondylitis (AS) (also known as Bekhterev's disease, Bekhterev syndrome, and Marie-Strumpell diseases)
  • AS ankylosing spondylitis
  • diseases of the central nervous system such as stroke
  • pulmonary diseases such as bronchitis obliterous and primary and primary pulmonary hypertension, delayed or cell-mediated
  • Type IV hypersensitivity such as leukemias and lymphomas.
  • the compound of the invention inhibits one or more components of a tyrosine kinase signaling cascade.
  • a compound of the invention inhibits JAK.
  • JAK is JAK3.
  • a compound of the invention inhibits SYK.
  • a compound of the invention inhibits BTK.
  • a compound of the invention inhibits JAK and SYK.
  • a compound of the invention inhibits JAK and BTK.
  • a compound of the invention inhibits BTK and SYK.
  • a compound of the invention inhibits JAK, SYK and BTK.
  • a compound of the invention inhibits JAK3 and has no activity on JAK2.
  • regulation of the immune system occurs through the inhibition of lymphocyte proliferation.
  • regulation of the immune system occurs through the inhibition of lymphocyte activation.
  • T-cell proliferation and/or activation is inhibited.
  • B-cell proliferation and/or activation is inhibited.
  • the subject is a mammal, e.g., a human.
  • the administration of a compound of the invention is carried out orally, parentally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by intracavitary or intravesical instillation, topically, intraarterially, intralesionally, by metering pump, or by application to mucous membranes.
  • a compound of the invention is administered with a pharmaceutically acceptable carrier.
  • the compound of the invention may be a JAK kinase inhibitor (e.g. , a JAK3 inhibitor).
  • the compound of the invention may inhibit a JAK kinase directly, or it may affect the JAK kinase pathway.
  • the compound of the invention may be a SYK inhibitor.
  • the compound of the invention may inhibit SYK directly or it may affect the SYK pathway.
  • the compound of the invention may be a BTK inhibitor.
  • the compound of the invention may inhibit BTK directly or it may affect the BTK pathway.
  • the cell proliferation disorder includes any type of cancer including solid tumors and non-solid tumors.
  • the solid tumors are selected from tumors in the CNS (central nervous system), liver cancer, colorectal carcinoma, breast cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical carcinoma, head and neck tumors, vulvar cancer and dermatological neoplasms including melanoma, squamous cell carcinoma and basal cell carcinomas.
  • non-solid tumors include lymphoproliferative disorders including leukemias and lymphomas.
  • the disorder is metastatic disease.
  • a compound of the invention also may be used in the treatment of a cancer or cell proliferation disorder in a combination therapy with one or more of anti-cancer treatments such as surgery, radiation therapy, immunotherapy and/or one or more anti-cancer agents selected from the group consisting of anti-proliferative agents, agents that modulate the cancer cell metabolism, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • anti-cancer treatments such as surgery, radiation therapy, immunotherapy and/or one or more anti-cancer agents selected from the group consisting of anti-proliferative agents, agents that modulate the cancer cell metabolism, cytotoxic agents, cytostatic agents, and chemotherapeutic agents and salts and derivatives thereof.
  • a compound of the invention may be used in the treatment of a cancer or cell proliferation disorder in combination therapy with any one of the drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, a Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • drugs selected from a group consisting of an alkaloid, an alkylating agent, an antitumor antibiotic, an antimetabolite, a Bcr-Abl tyrosine kinase inhibitor, a nucleoside analogue, a multidrug resistance reversing agent, a DNA binding agent, microtubule binding drug, a toxin and a DNA antagonist.
  • drugs selected from a group consisting of an alkaloid, an alkylating agent, an
  • a compound of the invention may enhance (e.g ., synergize) the activity of these agents. Further, such synergism would permit a compound of the invention, additional anti-proliferation agents, or both to be administered at lower dosages, and/or may significantly enhance the anti-proliferation properties of a compound at any given dose.
  • a compound of the invention refers to a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV or XV or a compound in Table A, Table B, or Table C.
  • the reference is being made to both the free base and the corresponding salts, solvates, polymorphs, and prodrugs thereof provided that such is possible and/or appropriate under the circumstances.
  • inhibitors refer to inhibitory, activating, or modulating molecules, respectively.
  • Inhibitors according to the present invention include a compound of the invention or a composition that inhibits expression of one or more components of a tyrosine protein kinase signaling cascade, such as a JAK kinase signaling cascade (e.g., JAK3), a SYK signaling cascade, and/or a BTK signaling cascade or bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the activity of one or more components of a protein kinase signaling cascade, such as a JAK kinase signaling cascade (e.g., JAK3), a SYK signaling cascade, and/or a BTK signaling cascade.
  • a JAK kinase signaling cascade e.g., JAK3
  • SYK signaling cascade e.g., SYK
  • Samples or assays comprising one or more components of a protein kinase signaling cascade, such as a JAK kinase signaling cascade (e.g., JAK3), SYK signaling cascade, and/or BTK signaling cascade can be treated with a compound of the invention and compared to control samples without a compound of the invention.
  • Control samples untreated with a compound of the invention
  • inhibition of one or more components of a protein kinase signaling cascade is achieved when the activity value relative to the control is about 80% or less.
  • Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
  • Treating or “treatment” of a disease state includes: (1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms or (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms.
  • Preventing means causing the clinical symptoms of the disease state not to develop, i.e., inhibiting the onset of disease, in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
  • Disease state means any disease, disorder, condition, symptom, or indication.
  • cell proliferative disorder and “cell proliferation-related disorder” refer to conditions in which the unregulated and/or abnormal growth of cells can lead to the development of an unwanted condition or disease, which can be cancerous or non-cancerous, for example a psoriatic condition.
  • the cell proliferation disorder is cancer.
  • cancer includes solid tumors, such as lung, breast, colon, ovarian, brain, liver, pancreas, prostate, malignant melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or malignancies, such as childhood leukemia and lymphomas, multiple myeloma, Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute and chronic leukemia such as acute lymphoblastic, myelofibrosis, acute myelocytic or chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and cancers associated with AIDS.
  • an "effective amount" of a compound is the quantity which, when administered to a subject having a disease or disorder, results in regression of the disease or disorder in the subject.
  • an effective amount of a compound of the invention is the quantity which, when administered to a subject having a cell proliferation disorder, results in regression of cell growth in the subject.
  • the amount of the compound of the invention to be administered to a subject will depend on the particular disorder, the mode of administration, co-administered compounds, if any, and the characteristics of the subject, such as general health, other diseases, age, sex, genotype, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • a therapeutically effective amount means the amount of a compound that, when administered to a mammal, e.g ., a human, for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
  • a therapeutically effective amount of one or more of the compounds can be formulated with a pharmaceutically acceptable carrier for administration to a human or an animal. Accordingly, a compound of the invention or a formulation thereof can be administered, for example, via oral, parenteral, or topical routes, to provide an effective amount of the compound. In on aspect, a compound of the invention can be used to coat or impregnate a medical device, e.g., a stent.
  • prophylactically effective amount means an effective amount of a compound of the invention that is administered to prevent or reduce the risk of a disease state.
  • “Pharmacological effect” as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy.
  • crystalline as used herein, means having a regularly repeating arrangement of molecules or external face planes.
  • crystalline purity means percentage of a crystalline compound in a sample which may contain an amorphous form of the same compound, at least one other crystalline form of the compound or a mixture thereof.
  • 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt has a crystalline purity of about 97.0%, 99.0%, 100% crystalline purity.
  • a polymorph can exist in either a hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • Non-limiting examples of hydrates include monohydrates, dihydrates, etc.
  • Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.
  • a "polymorph of the invention” as used herein means 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide hydrochloride salt (Form I) or 2-morpholino-N-(3-(4-(5-(pyrrolidine-1-carbonyl)-1H-pyrrol-3-yl)thiazol-2-yl)phenyl)acetamide (Form I).
  • Solvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some polymorphs have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • 2 hydrogens on the atom are replaced.
  • Keto substituents are not present on aromatic moieties.
  • the invention is intended to include all isotopes of atoms occurring in the compounds of the invention.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include C-13 and C-14.
  • the compounds of the invention described herein may have asymmetric centers.
  • any variable e.g ., R d
  • its definition at each occurrence is independent of its definition at every other occurrence.
  • R d the group may optionally be substituted with up to two R d moieties and R d at each occurrence is selected independently from the definition of R d .
  • substituents and/or variables are permissible, but only if such combinations result in stable compounds.
  • C 1-6 alkyl is meant to include alkyl groups with 1, 2, 3, 4, 5, 6, 1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and 5-6 carbons.
  • alkyl is intended to include both branched and straight-chain (linear) saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • C 1-6 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , and C 6 alkyl groups.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n-hexyl.
  • a straight chain or branched chain alkyl has six or fewer carbon atoms in its backbone (e.g ., C 1 -C 6 for straight chain, C 3 -C 6 for branched chain), and in other embodiments, a straight chain (linear) or branched chain alkyl has four or fewer carbon atoms.
  • C 3 -C 8 cycloalkyl has from three to eight carbon atoms in the ring structure, and in other embodiments, "C 5 -C 6 cycloalkyl” has five or six carbons in the ring structure.
  • lower alkyl includes an alkyl group, as defined above, but having from one to ten, or in other embodiments from one to six, carbon atoms in its backbone structure.
  • Lower alkenyl and “lower alkynyl” have chain lengths of, for example, 2-6 carbon atoms.
  • substituted alkyl refers to alkyl moieties having substituents replacing a hydrogen atom on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbam
  • Cycloalkyls can be further substituted, e.g ., with the substituents described above.
  • An "alkylaryl” or an “aralkyl” moiety is an alkyl substituted with an aryl ( e.g ., phenylmethyl (benzyl)).
  • alkenyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double bond.
  • alkenyl includes straight-chain (linear) alkenyl groups (e.g ., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain alkenyl groups, cycloalkenyl (e.g., alicyclic) groups ( e.g., cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or cycloalkenyl substituted alkenyl groups.
  • a straight chain or branched chain alkenyl group has six or fewer carbon atoms in its backbone (e.g ., C 2 -C 6 for straight chain (linear), C 3 -C 6 for branched chain).
  • cycloalkenyl groups may have from three to eight carbon atoms in their ring structure, and in some embodiments, cycloalkenyl groups have five or six carbons in the ring structure.
  • C 2 -C 6 includes alkenyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkenyl groups containing three to six carbon atoms.
  • substituted alkenyl refers to alkenyl moieties having substituents replacing a hydrogen atom on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbam
  • Alkynyl includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond.
  • alkynyl includes straight-chain alkynyl groups (e.g ., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl groups.
  • a straight chain or branched chain alkynyl group has six or fewer carbon atoms in its backbone (e.g ., C 2 -C 6 for straight chain, C 3 -C 6 for branched chain).
  • C 2 -C 6 includes alkynyl groups containing two to six carbon atoms.
  • C 3 -C 6 includes alkynyl groups containing three to six carbon atoms.
  • substituted alkynyl refers to alkynyl moieties having substituents replacing a hydrogen atom on one or more hydrocarbon backbone carbon atoms.
  • substituents can include, for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino,
  • Aryl includes phenyl and naphthyl.
  • Aryl rings can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino,
  • halo or halogen refers to fluoro, chloro, bromo, and iodo.
  • perhalogenated generally refers to a moiety wherein all hydrogens are replaced by halogen atoms.
  • Carbocycle or “carbocyclic ring” is intended to mean any stable monocyclic, bicyclic, or tricyclic ring having the specified number of carbons, any of which may be saturated, unsaturated, or aromatic.
  • a C 3-14 carbocycle is intended to mean a mono-, bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms.
  • carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
  • Bridged rings are also included in the definition of carbocycle, including, for example, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and [2.2.2]bicyclooctane.
  • a bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms.
  • bridge rings are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.
  • Fused e.g., naphthyl and tetrahydronaphthyl
  • spiro rings are also included.
  • heterocycle or “heterocyclic” is intended to mean any stable monocyclic, bicyclic, or tricyclic ring which is saturated, unsaturated, or aromatic and comprises carbon atoms and one or more ring heteroatoms, e.g ., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • a bicyclic or tricyclic heterocycle may have one or more heteroatoms located in one ring, or the heteroatoms may be located in more than one ring.
  • a nitrogen atom When a nitrogen atom is included in the ring it is either N or NH, depending on whether or not it is attached to a double bond in the ring (i.e., a hydrogen is present if needed to maintain the tri-valency of the nitrogen atom).
  • the nitrogen atom may be substituted or unsubstituted ( i.e., N or NR wherein R is H or another substituent, as defined).
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • a nitrogen in the heterocycle may optionally be quaternized.
  • Bridged rings are also included in the definition of heterocycle.
  • a bridged ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Bridges include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge. Spiro and fused rings are also included.
  • heterocycloalkyl is intended to mean any stable monocyclic, bicyclic, or tricyclic ring which is saturated and comprises carbon atoms and one or more ring heteroatoms, e.g ., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • aromatic heterocycle or “heteroaryl” is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic aromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclic aromatic heterocyclic ring which consists of carbon atoms and one or more heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • bicyclic heterocyclic aromatic rings only one of the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both may be ( e.g., quinoline).
  • the second ring can also be fused or bridged as defined above for heterocycles.
  • the nitrogen atom may be substituted or unsubstituted (i.e ., N or NR wherein R is H or another substituent, as defined).
  • heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4a H- carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2 H ,6 H -1,5,2-dithiazinyl, dihydrofuro[2,3- b ]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1 H -indazolyl, in
  • acyl refers to the acyl radical (CH 3 CO-).
  • substituted acyl includes acyl groups where one or more of the hydrogen atoms are replaced by for example, alkyl groups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and
  • Acylamino includes moieties wherein an acyl moiety is bonded to an amino group.
  • the term includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.
  • Aroyl includes compounds and moieties with an aryl or heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups include phenylcarboxy, naphthyl carboxy, etc.
  • Alkoxyalkyl examples include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms, e.g., oxygen, nitrogen or sulfur atoms.
  • alkoxy or "alkoxyl” includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom.
  • alkoxy groups or alkoxyl radicals
  • alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.
  • substituted alkoxy groups include halogenated alkoxy groups.
  • the alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxy
  • thiocarbonyl or "thiocarboxy” includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.
  • ether or "alkoxy” includes compounds or moieties which contain an oxygen bonded to two different carbon atoms or heteroatoms.
  • alkoxyalkyl which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to another alkyl group.
  • esters includes compounds and moieties which contain a carbon or a heteroatom bound to an oxygen atom which is bonded to the carbon of a carbonyl group.
  • ester includes alkoxycarboxy groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, etc.
  • alkyl, alkenyl, or alkynyl groups are as defined above.
  • thioether includes compounds and moieties which contain a sulfur atom bonded to two different carbon or heteroatoms.
  • examples of thioethers include, but are not limited to alkthioalkyls, alkthioalkenyls, and alkthioalkynyls.
  • alkthioalkyls include compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group.
  • alkthioalkenyls and alkthioalkynyls refer to compounds or moieties wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.
  • hydroxy or "hydroxyl” refers to the group -OH.
  • Polycyclyl or “polycyclic radical” refers to two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings. Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urei
  • the structural formula of the compound represents a certain isomer for convenience in some cases, but the invention includes all isomers such as geometrical isomer, optical isomer based on an asymmetrical carbon, stereoisomer, tautomer and the like which occur structurally and an isomer mixture and is not limited to the description of the formula for convenience, and may be any one isomer or a mixture. Therefore, an asymmetrical carbon atom may be present in the molecule and an optically active compound and a racemic compound may be present in the compound, but the invention is not limited to them and includes any one.
  • a crystal polymorphism may be present but is not limiting, but any crystal form may be single or a crystal form mixture, or an anhydride or hydrate. Further, so-called metabolite which is produced by degradation of the compound in vivo is included in the scope of the invention.
  • “Isomerism” means compounds that have identical molecular formula but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a "chiral center".
  • Chiral isomer means a compound with at least one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture”. A compound that has more than one chiral center has 2 n-1 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture”.
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. ( Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385 ; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413 ; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612 ; Cahn et al., Experientia 1956, 12, 81 ; Cahn, J., Chem. Educ. 1964,41, 116 ).
  • “Geometric Isomer” means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
  • a compound of the invention includes all atropic isomers thereof.
  • “Atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances in chromatography, it has been possible to separate mixtures of two atropic isomers in select cases.
  • crystal polymorph or “polymorph” or “crystal form” means crystal structures in which a compound of the invention can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectral, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Crystal polymorphs of a compound of the invention can be prepared by crystallization under different conditions.
  • a compound of the invention for example, a salt of a compound of the invention, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules.
  • hydrates include monohydrates, dihydrates, etc.
  • solvates include ethanol solvates, acetone solvates, etc.
  • Solvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H 2 O, such combination being able to form one or more hydrate.
  • Tautomer refers to compounds whose structures differ markedly in arrangement of atoms, but which exist in easy and rapid equilibrium. It is to be understood that the compounds of the invention may be depicted as different tautomers. It should also be understood that when a compound of the invention has tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any tautomer form.
  • a compound of the invention can exist in several tautomeric forms, including the enol and imine form, and the keto and enamine form and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the invention. Tautomers exist as mixtures of a tautomeric set in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the invention includes all tautomers of the compound.
  • a tautomer is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This reaction results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertable by tautomerizations is called tautomerism.
  • keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs.
  • Ring-chain tautomerism is exhibited by glucose. It arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form.
  • Tautomerizations are catalyzed by: Base: 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion; Acid: 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Base 1. deprotonation; 2. formation of a delocalized anion (e.g. an enolate); 3. protonation at a different position of the anion
  • Acid 1. protonation; 2. formation of a delocalized cation; 3. deprotonation at a different position adjacent to the cation.
  • Common tautomeric pairs are: ketone - enol, amide - nitrile, lactam - lactim, amide - imidic acid tautomerism in heterocyclic rings (e.g. in the nucleobases guanine, thymine, and cytosine), amine - enamine and enamine - enamine.
  • a compound of the invention may include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes can include either the E- or Z-geometry, where appropriate. A compound of the invention may exist in stereoisomeric form, therefore can be produced as individual stereoisomers or as mixtures.
  • analog refers to a compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group).
  • an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.
  • the term "derivative” refers to a compound that has a common core structure and is substituted with various groups as described herein.
  • all of the compounds represented by Formula IV are 4-(thiazol-4-yl)-1 H -pyrrole-2-carboxamide derivatives and have 4-(thiazol-4-yl)-1 H- pyrrole-2-carboxamide as a common core.
  • a "pharmaceutical composition” is a formulation containing compounds in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial.
  • the quantity of active ingredient (e.g., a formulation of a compound of the invention or a salt, solvate, polymorph, or prodrug thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of a compound of the invention or a salt, solvate, polymorph, or prodrug thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • flash dose refers to compound formulations that are rapidly dispersing dosage forms.
  • immediate release is defined as a release of compound from a dosage form in a relatively brief period of time, generally up to about 60 minutes.
  • modified release is defined to include delayed release, extended release, and pulsed release.
  • pulsed release is defined as a series of releases of drug from a dosage form.
  • a "subject” includes mammals, e.g., humans, companion animals (e.g., dogs, cats, birds, and the like), farm animals (e.g., cows, sheep, pigs, horses, fow1, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, birds, and the like). In some embodiments, the subject is human.
  • companion animals e.g., dogs, cats, birds, and the like
  • farm animals e.g., cows, sheep, pigs, horses, fow1, and the like
  • laboratory animals e.g., rats, mice, guinea pigs, birds, and the like.
  • the subject is human.
  • the phrase "pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a "pharmaceutically acceptable excipient” as used herein includes both one and more than one such excipient.
  • a compound of the invention is capable of further forming salts. All of these forms are also contemplated within the scope of the invention.
  • “Pharmaceutically acceptable salt” of a compound of the invention means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • pharmaceutically acceptable salts refer to derivatives of a compound of the invention, where the parent compound is modified by making acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic, 2-hydroxyethane sulfonic, acetic, ascorbic, benzene sulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, 1,2-ethane sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycollyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, mandelic, methane sulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric,
  • hexanoic acid cyclopentane propionic acid
  • pyruvic acid malonic acid
  • 3-(4-hydroxybenzoyl)benzoic acid cinnamic acid
  • 4-chlorobenzenesulfonic acid 2-naphthalenesulfonic acid
  • 4-toluenesulfonic acid camphorsulfonic acid
  • 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, and the like.
  • the invention also encompasses salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
  • Solid compound and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the invention provides compounds for use for the treatment of a cell proliferative disorder.
  • the cell proliferative disorder can be cancer or a precancerous condition..
  • the invention also provides compounds for use for protecting against a cell proliferative disorder.
  • the cell proliferative disorder can be cancer or a precancerous condition..
  • a "subject in need thereof” is a subject having a cell proliferative disorder, or a subject having an increased risk of developing a cell proliferative disorder relative to the population at large.
  • a subject in need thereof can have a precancerous condition.
  • a subject in need thereof has cancer.
  • a "subject” includes a mammal.
  • the mammal can be e.g., any mammal, e.g., a human, primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or a pig.
  • the mammal is a human.
  • cell proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • Exemplary cell proliferative disorders of the invention encompass a variety of conditions wherein cell division is deregulated.
  • Exemplary cell proliferative disorder include, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.
  • a cell proliferative disorder includes a precancer or a precancerous condition.
  • a cell proliferative disorder includes cancer.
  • the compounds provided herein are used to treat or alleviate a symptom of cancer.
  • cancer includes solid tumors, as well as, hematologic tumors and/or malignancies.
  • precancer cell or “precancerous cell” is a cell manifesting a cell proliferative disorder that is a precancer or a precancerous condition.
  • cancer cell or "cancerous cell” is a cell manifesting a cell proliferative disorder that is a cancer. Any reproducible means of measurement may be used to identify cancer cells or precancerous cells. Cancer cells or precancerous cells can be identified by histological typing or grading of a tissue sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be identified through the use of appropriate molecular markers.
  • non-cancerous conditions or disorders include, but are not limited to, rheumatoid arthritis; psoriatic arthritis, inflammation; autoimmune disease; dry eye disease, lymphoproliferative conditions; acromegaly; rheumatoid spondylitis; osteoarthritis; gout, other arthritic conditions; sepsis; septic shock; endotoxic shock; gram-negative sepsis; toxic shock syndrome; asthma; adult respiratory distress syndrome; chronic obstructive pulmonary disease; chronic pulmonary inflammation; inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease); psoriasis; eczema; pancreatic fibrosis; hepatic fibrosis; acute and chronic renal disease; irritable bowel syndrome; pyresis; restenosis; cerebral malaria; stroke and ischemic injury; neural trauma; Alzheimer's disease; Huntington's disease; Parkinson's disease; acute and chronic pain; allergic rhin
  • Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, uringary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodeimal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas
  • a “cell proliferative disorder of the hematologic system” is a cell proliferative disorder involving cells of the hematologic system.
  • a cell proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid papulosis, polycythemia vera (erythremia), chronic myelocytic leukemia, agnogenic myeloid metaplasia, and essential thrombocythemia.
  • a cell proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system.
  • a composition of the invention may be used to treat a cancer selected from the group consisting of a hematologic cancer of the present invention or a hematologic cell proliferative disorder of the present invention.
  • a hematologic cancer of the present invention can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.
  • lymphoma including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin
  • leukemia including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic
  • a "cell proliferative disorder of the lung” is a cell proliferative disorder involving cells of the lung.
  • Cell proliferative disorders of the lung can include all forms of cell proliferative disorders affecting lung cells.
  • Cell proliferative disorders of the lung can include lung cancer, a precancer or precancerous condition of the lung, benign growths or lesions of the lung, and malignant growths or lesions of the lung, and metastatic lesions in tissue and organs in the body other than the lung.
  • Compositions of the invention may be used to treat lung cancer or cell proliferative disorders of the lung.
  • Lung cancer can include all forms of cancer of the lung.
  • Lung cancer can include malignant lung neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors.
  • Lung cancer can include small cell lung cancer ("SCLC"), non-small cell lung cancer ("NSCLC”), squamous cell carcinoma, adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous cell carcinoma, and mesothelioma.
  • Lung cancer can include "scar carcinoma", bronchioalveolar carcinoma, giant cell carcinoma, spindle cell carcinoma, and large cell neuroendocrine carcinoma.
  • Lung cancer can include lung neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types).
  • Cell proliferative disorders of the lung can include all forms of cell proliferative disorders affecting lung cells.
  • Cell proliferative disorders of the lung can include lung cancer, precancerous conditions of the lung.
  • Cell proliferative disorders of the lung can include hyperplasia, metaplasia, and dysplasia of the lung.
  • Cell proliferative disorders of the lung can include asbestos-induced hyperplasia, squamous metaplasia, and benign reactive mesothelial metaplasia.
  • Cell proliferative disorders of the lung can include replacement of columnar epithelium with stratified squamous epithelium, and mucosal dysplasia.
  • Prior lung diseases that may predispose individuals to development of cell proliferative disorders of the lung can include chronic interstitial lung disease, necrotizing pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis, interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and Hodgkin's disease.
  • a "cell proliferative disorder of the colon” is a cell proliferative disorder involving cells of the colon.
  • the cell proliferative disorder of the colon is colon cancer.
  • Compositions of the invention may be used to treat colon cancer or cell proliferative disorders of the colon.
  • Colon cancer can include all forms of cancer of the colon.
  • Colon cancer can include sporadic and hereditary colon cancers.
  • Colon cancer can include malignant colon neoplasms, carcinoma in situ, typical carcinoid tumors, and atypical carcinoid tumors.
  • Colon cancer can include adenocarcinoma, squamous cell carcinoma, and adenosquamous cell carcinoma.
  • Colon cancer can be associated with a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • Colon cancer can be caused by a hereditary syndrome selected from the group consisting of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's syndrome, Koz-Jeghers syndrome, Turcot's syndrome and juvenile polyposis.
  • Cell proliferative disorders of the colon can include all forms of cell proliferative disorders affecting colon cells.
  • Cell proliferative disorders of the colon can include colon cancer, precancerous conditions of the colon, adenomatous polyps of the colon and metachronous lesions of the colon.
  • a cell proliferative disorder of the colon can include adenoma.
  • Cell proliferative disorders of the colon can be characterized by hyperplasia, metaplasia, and dysplasia of the colon.
  • Prior colon diseases that may predispose individuals to development of cell proliferative disorders of the colon can include prior colon cancer.
  • Current disease that may predispose individuals to development of cell proliferative disorders of the colon can include Crohn's disease and ulcerative colitis.
  • a cell proliferative disorder of the colon can be associated with a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • An individual can have an elevated risk of developing a cell proliferative disorder of the colon due to the presence of a mutation in a gene selected from the group consisting of p53, ras, FAP and DCC.
  • a "cell proliferative disorder of the pancreas” is a cell proliferative disorder involving cells of the pancreas.
  • Cell proliferative disorders of the pancreas can include all forms of cell proliferative disorders affecting pancreatic cells.
  • Cell proliferative disorders of the pancreas can include pancreas cancer, a precancer or precancerous condition of the pancreas, hyperplasia of the pancreas, and dysaplasia of the pancreas, benign growths or lesions of the pancreas, and malignant growths or lesions of the pancreas, and metastatic lesions in tissue and organs in the body other than the pancreas.
  • Pancreatic cancer includes all forms of cancer of the pancreas.
  • Pancreatic cancer can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous cystadenoma.
  • Pancreatic cancer can also include pancreatic neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types).
  • a "cell proliferative disorder of the prostate” is a cell proliferative disorder involving cells of the prostate.
  • Cell proliferative disorders of the prostate can include all forms of cell proliferative disorders affecting prostate cells.
  • Cell proliferative disorders of the prostate can include prostate cancer, a precancer or precancerous condition of the prostate, benign growths or lesions of the prostate, and malignant growths or lesions of the prostate, and metastatic lesions in tissue and organs in the body other than the prostate.
  • Cell proliferative disorders of the prostate can include hyperplasia, metaplasia, and dysplasia of the prostate.
  • a "cell proliferative disorder of the skin” is a cell proliferative disorder involving cells of the skin.
  • Cell proliferative disorders of the skin can include all forms of cell proliferative disorders affecting skin cells.
  • Cell proliferative disorders of the skin can include a precancer or precancerous condition of the skin, benign growths or lesions of the skin, melanoma, malignant melanoma and other malignant growths or lesions of the skin, and metastatic lesions in tissue and organs in the body other than the skin.
  • Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of the skin.
  • a "cell proliferative disorder of the ovary” is a cell proliferative disorder involving cells of the ovary.
  • Cell proliferative disorders of the ovary can include all forms of cell proliferative disorders affecting cells of the ovary.
  • Cell proliferative disorders of the ovary can include a precancer or precancerous condition of the ovary, benign growths or lesions of the ovary, ovarian cancer, malignant growths or lesions of the ovary, and metastatic lesions in tissue and organs in the body other than the ovary.
  • Cell proliferative disorders of the skin can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.
  • a "cell proliferative disorder of the breast” is a cell proliferative disorder involving cells of the breast.
  • Cell proliferative disorders of the breast can include all forms of cell proliferative disorders affecting breast cells.
  • Cell proliferative disorders of the breast can include breast cancer, a precancer or precancerous condition of the breast, benign growths or lesions of the breast, and malignant growths or lesions of the breast, and metastatic lesions in tissue and organs in the body other than the breast.
  • Cell proliferative disorders of the breast can include hyperplasia, metaplasia, and dysplasia of the breast.
  • a cell proliferative disorder of the breast can be a precancerous condition of the breast.
  • Compositions of the present invention may be used to treat a precancerous condition of the breast.
  • a precancerous condition of the breast can include atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, and stage 0 or grade 0 growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ ).
  • a precancerous condition of the breast can be staged according to the TNM classification scheme as accepted by the American Joint Committee on Cancer (AJCC), where the primary tumor (T) has been assigned a stage of T0 or Tis; and where the regional lymph nodes (N) have been assigned a stage of N0; and where distant metastasis (M) has been assigned a stage of M0.
  • AJCC American Joint Committee on Cancer
  • the cell proliferative disorder of the breast can be breast cancer.
  • Breast cancer includes all forms of cancer of the breast.
  • Breast cancer can include primary epithelial breast cancers.
  • Breast cancer can include cancers in which the breast is involved by other tumors such as lymphoma, sarcoma or melanoma.
  • Breast cancer can include carcinoma of the breast, ductal carcinoma of the breast, lobular carcinoma of the breast, undifferentiated carcinoma of the breast, cystosarcoma phyllodes of the breast, angiosarcoma of the breast, and primary lymphoma of the breast.
  • Breast cancer can include Stage I, II, IIIA, IIIB, IIIC and IV breast cancer.
  • Ductal carcinoma of the breast can include invasive carcinoma, invasive carcinoma in situ with predominant intraductal component, inflammatory breast cancer, and a ductal carcinoma of the breast with a histologic type selected from the group consisting of comedo, mucinous (colloid), medullary, medullary with lymphcytic infiltrate, papillary, scirrhous, and tubular.
  • Lobular carcinoma of the breast can include invasive lobular carcinoma with predominant in situ component, invasive lobular carcinoma, and infiltrating lobular carcinoma.
  • Breast cancer can include Paget's disease, Paget's disease with intraductal carcinoma, and Paget's disease with invasive ductal carcinoma.
  • Breast cancer can include breast neoplasms having histologic and ultrastructual heterogeneity (e.g., mixed cell types).
  • a breast cancer that is to be treated can include familial breast cancer.
  • a breast cancer that is to be treated can include sporadic breast cancer.
  • a breast cancer that is to be treated can arise in a male subject.
  • a breast cancer that is to be treated can arise in a female subject.
  • a breast cancer that is to be treated can arise in a premenopausal female subject or a postmenopausal female subject.
  • a breast cancer that is to be treated can arise in a subject equal to or older than 30 years old, or a subject younger than 30 years old.
  • a breast cancer that is to be treated has arisen in a subject equal to or older than 50 years old, or a subject younger than 50 years old.
  • a breast cancer that is to be treated can arise in a subject equal to or older than 70 years old, or a subject younger than 70 years old.
  • a breast cancer that is to be treated can be typed to identify a familial or spontaneous mutation in BRCA1, BRCA2, or p53.
  • a breast cancer that is to be treated can be typed as having a HER2/neu gene amplification, as overexpressing HER2/neu, or as having a low, intermediate or high level of HER2/neu expression.
  • a breast cancer that is to be treated can be typed as HER2-negative or HER2-positive.
  • HER2-typing of a breast cancer may be performed by any reproducible means.
  • a breast cancer that is to be treated can be typed for a marker selected from the group consisting of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met.
  • a breast cancer that is to be treated can be typed as ER-unknown, ER-rich or ER-poor.
  • a breast cancer that is to be treated can be typed as ER-negative or ER-positive.
  • ER-typing of a breast cancer may be performed by any reproducible means.
  • ER-typing of a breast cancer may be performed as set forth in Onkologie 27: 175-179 (2004 ).
  • a breast cancer that is to be treated can be typed as PR-unknown, PR-rich or PR-poor.
  • a breast cancer that is to be treated can be typed as PR-negative or PR-positive.
  • PR-typing of a breast cancer may be performed by any reproducible means.
  • a breast cancer that is to be treated can be typed as receptor positive or receptor negative.
  • a breast cancer that is to be treated can have multiple receptors each independently typed as receptor positive or receptor negative.
  • a breast cancer that can be treated can be "a triple negative breast cancer” (i.e., typed as ER-negative, PR-negative, and HER2-negative).
  • a breast cancer that is to be treated can be typed as being associated with elevated blood levels of CA 15-3, or CA 27-29, or both.
  • a breast cancer that is to be treated can include a localized tumor of the breast.
  • a breast cancer that is to be treated can include a tumor of the breast that is associated with a negative sentinel lymph node (SLN) biopsy.
  • a breast cancer that is to be treated can include a tumor of the breast that is associated with a positive sentinel lymph node (SLN) biopsy.
  • a breast cancer that is to be treated can include a tumor of the breast that is associated with one or more positive axillary lymph nodes, where the axillary lymph nodes have been staged by any applicable method.
  • a breast cancer that is to be treated can include a tumor of the breast that has been typed as having nodal negative status (e.g., node-negative) or nodal positive status (e.g., node-positive).
  • a breast cancer that is to be treated can include a tumor of the breast that has metastasized to other locations in the body.
  • a breast cancer that is to be treated can be classified as having metastasized to a location selected from the group consisting of bone, lung, liver, or brain.
  • a breast cancer that is to be treated can be classified according to a characteristic selected from the group consisting of metastatic, localized, regional, local-regional, locally advanced, distant, multicentric, bilateral, ipsilateral, contralateral, newly diagnosed, recurrent, and inoperable.
  • a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof may be used to treat or prevent a cell proliferative disorder of the breast, or to treat or prevent breast cancer, in a subject having an increased risk of developing breast cancer relative to the population at large.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history or personal history of breast cancer.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female subject having a germ-line or spontaneous mutation in BRCA1 or BRCA2, or both.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female subject with a family history of breast cancer and a germ-line or spontaneous mutation in BRCA1 or BRCA2, or both.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a female who is greater than 30 years old, greater than 40 years old, greater than 50 years old, greater than 60 years old, greater than 70 years old, greater than 80 years old, or greater than 90 years old.
  • a subject with an increased risk of developing breast cancer relative to the population at large is a subject with atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular neoplasia, or a stage 0 growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ ).
  • DCIS ductal carcinoma in situ
  • LCIS lobular carcinoma in situ
  • lobular neoplasia or a stage 0 growth or lesion of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in situ ).
  • a breast cancer that is to be treated can histologically graded according to the Scarff-Bloom-Richardson system, wherein a breast tumor has been assigned a mitosis count score of 1, 2, or 3; a nuclear pleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or 3; and a total Scarff-Bloom-Richardson score of between 3 and 9.
  • a breast cancer that is to be treated can be assigned a tumor grade according to the International Consensus Panel on the Treatment of Breast Cancer selected from the group consisting of grade 1, grade 1-2, grade 2, grade 2-3, or grade 3.
  • a cancer that is to be treated can be staged according to the American Joint Committee on Cancer (AJCC) TNM classification system, where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b, Tic, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3, N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a stage of MX, M0, or M1.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be staged according to an American Joint Committee on Cancer (AJCC) classification as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or Stage IV.
  • AJCC American Joint Committee on Cancer
  • a cancer that is to be treated can be assigned a grade according to an AJCC classification as Grade GX (e.g., grade cannot be assessed), Grade 1, Grade 2, Grade 3 or Grade 4.
  • a cancer that is to be treated can be staged according to an AJCC pathologic classification (pN) of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi), PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.
  • pN AJCC pathologic classification
  • a cancer that is to be treated can include a tumor that has been determined to be less than or equal to about 2 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be from about 2 to about 5 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be greater than or equal to about 3 centimeters in diameter.
  • a cancer that is to be treated can include a tumor that has been determined to be greater than 5 centimeters in diameter.
  • a cancer that is to be treated can be classified by microscopic appearance as well differentiated, moderately differentiated, poorly differentiated, or undifferentiated.
  • a cancer that is to be treated can be classified by microscopic appearance with respect to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism (e.g., change in cells).
  • a cancer that is to be treated can be classified by microscopic appearance as being associated with areas of necrosis (e.g., areas of dying or degenerating cells).
  • a cancer that is to be treated can be classified as having an abnormal karyotype, having an abnormal number of chromosomes, or having one or more chromosomes that are abnormal in appearance.
  • a cancer that is to be treated can be classified as being aneuploid, triploid, tetraploid, or as having an altered ploidy.
  • a cancer that is to be treated can be classified as having a chromosomal translocation, or a deletion or duplication of an entire chromosome, or a region of deletion, duplication or amplification of a portion of a chromosome.
  • a cancer that is to be treated can be evaluated by DNA cytometry, flow cytometry, or image cytometry.
  • a cancer that is to be treated can be typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells in the synthesis stage of cell division (e.g., in S phase of cell division).
  • a cancer that is to be treated can be typed as having a low S-phase fraction or a high S-phase fraction.
  • a "normal cell” is a cell that cannot be classified as part of a "cell proliferative disorder”.
  • a normal cell lacks unregulated or abnormal growth, or both, that can lead to the development of an unwanted condition or disease.
  • a normal cell possesses normally functioning cell cycle checkpoint control mechanisms.
  • contacting a cell refers to a condition in which a compound or other composition of matter is in direct contact with a cell, or is close enough to induce a desired biological effect in a cell.
  • candidate compound refers to a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, that has been or will be tested in one or more in vitro or in vivo biological assays, in order to determine if that compound is likely to elicit a desired biological or medical response in a cell, tissue, system, animal or human that is being sought by a researcher or clinician.
  • a candidate compound is a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof.
  • the biological or medical response can be the treatment of cancer.
  • the biological or medical response can be treatment or prevention of a cell proliferative disorder.
  • In vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.
  • monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of an active compound.
  • cancer monotherapy with one of the compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof to a subject in need of treatment of cancer.
  • Monotherapy may be contrasted with combination therapy, in which a combination of multiple active compounds is administered or with each component of the combination present in a therapeutically effective amount.
  • monotherapy with a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof is more effective than combination therapy in inducing a desired biological effect.
  • treating describes the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder.
  • a compound of the invention can also be used to prevent a disease, condition or disorder.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • the term "alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
  • a sign or symptom can be alleviated without being eliminated.
  • the administration of pharmaceutical compositions of the invention leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • severity is meant to describe the potential of cancer to transform from a precancerous, or benign, state into a malignant state.
  • severity is meant to describe a cancer stage, for example, according to the TNM system (accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)) or by other art-recognized methods.
  • TNM system accepted by the International Union against Cancer (UICC) and the American Joint Committee on Cancer (AJCC)
  • UNM system International Union against Cancer
  • AJCC American Joint Committee on Cancer
  • Cancer stage refers to the extent or severity of the cancer, based on factors such as the location of the primary tumor, tumor size, number of tumors, and lymph node involvement (spread of cancer into lymph nodes).
  • Tumor grade is a system used to classify cancer cells in terms of how abnormal they look under a microscope and how quickly the tumor is likely to grow and spread. Many factors are considered when determining tumor grade, including the structure and growth pattern of the cells. The specific factors used to determine tumor grade vary with each type of cancer. Severity also describes a histologic grade, also called differentiation, which refers to how much the tumor cells resemble normal cells of the same tissue type (see, National Cancer Institute, www.cancer.gov). Furthermore, severity describes a nuclear grade, which refers to the size and shape of the nucleus in tumor cells and the percentage of tumor cells that are dividing (see, National Cancer Institute, www.cancer.gov).
  • severity describes the degree to which a tumor has secreted growth factors, degraded the extracellular matrix, become vascularized, lost adhesion to juxtaposed tissues, or metastasized. Moreover, severity describes the number of locations to which a primary tumor has metastasized. Finally, severity includes the difficulty of treating tumors of varying types and locations. For example, inoperable tumors, those cancers which have greater access to multiple body systems (hematological and immunological tumors), and those which are the most resistant to traditional treatments are considered most severe.
  • symptom is defined as an indication of disease, illness, injury, or that something is not right in the body. Symptoms are felt or noticed by the individual experiencing the symptom, but may not easily be noticed by others. Others are defined as non-health-care professionals.
  • signs are also defined as an indication that something is not right in the body. But signs are defined as things that can be seen by a doctor, nurse, or other health care professional.
  • Cancer is a group of diseases that may cause almost any sign or symptom. The signs and symptoms will depend on where the cancer is, the size of the cancer, and how much it affects the nearby organs or structures. If a cancer spreads (metastasizes), then symptoms may appear in different parts of the body.
  • cancer As a cancer grows, it begins to push on nearby organs, blood vessels, and nerves. This pressure creates some of the signs and symptoms of cancer. If the cancer is in a critical area, such as certain parts of the brain, even the smallest tumor can cause early symptoms.
  • pancreas cancers for example, do not usually grow large enough to be felt from the outside of the body. Some pancreatic cancers do not cause symptoms until they begin to grow around nearby nerves (this causes a backache). Others grow around the bile duct, which blocks the flow of bile and leads to a yellowing of the skin known as jaundice. By the time a pancreatic cancer causes these signs or symptoms, it has usually reached an advanced stage.
  • a cancer may also cause symptoms such as fever, fatigue, or weight loss. This may be because cancer cells use up much of the body's energy supply or release substances that change the body's metabolism. Or the cancer may cause the immune system to react in ways that produce these symptoms.
  • cancer cells release substances into the bloodstream that cause symptoms not usually thought to result from cancers.
  • some cancers of the pancreas can release substances which cause blood clots to develop in veins of the legs.
  • Some lung cancers make hormone-like substances that affect blood calcium levels, affecting nerves and muscles and causing weakness and dizziness
  • Cancer presents several general signs or symptoms that occur when a variety of subtypes of cancer cells are present. Most people with cancer will lose weight at some time with their disease. An unexplained (unintentional) weight loss of 10 pounds or more may be the first sign of cancer, particularly cancers of the pancreas, stomach, esophagus, or lung.
  • Fever is very common with cancer, but is more often seen in advanced disease. Almost all patients with cancer will have fever at some time, especially if the cancer or its treatment affects the immune system and makes it harder for the body to fight infection. Less often, fever may be an early sign of cancer, such as with leukemia or lymphoma.
  • Fatigue may be an important symptom as cancer progresses. It may happen early, though, in cancers such as with leukemia, or if the cancer is causing an ongoing loss of blood, as in some colon or stomach cancers.
  • cancer subtypes present specific signs or symptoms. Changes in bowel habits or bladder function could indicate cancer. Long-term constipation, diarrhea, or a change in the size of the stool may be a sign of colon cancer. Pain with urination, blood in the urine, or a change in bladder function (such as more frequent or less frequent urination) could be related to bladder or prostate cancer.
  • Skin cancers may bleed and look like sores that do not heal.
  • a long-lasting sore in the mouth could be an oral cancer, especially in patients who smoke, chew tobacco, or frequently drink alcohol. Sores on the penis or vagina may either be signs of infection or an early cancer.
  • Unusual bleeding or discharge could indicate cancer. Unusual bleeding can happen in either early or advanced cancer. Blood in the sputum (phlegm) may be a sign of lung cancer. Blood in the stool (or a dark or black stool) could be a sign of colon or rectal cancer. Cancer of the cervix or the endometrium (lining of the uterus) can cause vaginal bleeding. Blood in the urine may be a sign of bladder or kidney cancer. A bloody discharge from the nipple may be a sign of breast cancer.
  • a thickening or lump in the breast or in other parts of the body could indicate the presence of a cancer. Many cancers can be felt through the skin, mostly in the breast, testicle, lymph nodes (glands), and the soft tissues of the body. A lump or thickening may be an early or late sign of cancer. Any lump or thickening could be indicative of cancer, especially if the formation is new or has grown in size.
  • Indigestion or trouble swallowing could indicate cancer. While these symptoms commonly have other causes, indigestion or swallowing problems may be a sign of cancer of the esophagus, stomach, or pharynx (throat).
  • Wart or mole could be indicative of cancer. Any wart, mole, or freckle that changes in color, size, or shape, or loses its definite borders indicates the potential development of cancer.
  • the skin lesion may be a melanoma.
  • a persistent cough or hoarseness could be indicative of cancer.
  • a cough that does not go away may be a sign of lung cancer.
  • Hoarseness can be a sign of cancer of the larynx (voice box) or thyroid.
  • Treating cancer can result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as "tumor regression".
  • tumor size is reduced by about 5% or greater relative to its size prior to treatment; tumor size is reduced by about 10% or greater; reduced by about 20% or greater; reduced by about 30% or greater; reduced by about 40% or greater; reduced by about 50% or greater; and reduced by about greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer can result in a reduction in tumor volume.
  • tumor volume is reduced by about 5% or greater relative to its size prior to treatment; tumor volume is reduced by about 10% or greater; reduced by about 20% or greater; reduced by about 30% or greater; reduced by about 40% or greater; reduced by about 50% or greater; and reduced by greater than about 75% or greater.
  • Tumor volume may be measured by any reproducible means of measurement.
  • Treating cancer results in a decrease in number of tumors.
  • tumor number is reduced by about 5% or greater relative to number prior to treatment; tumor number is reduced by about 10% or greater; reduced by about 20% or greater; reduced by about 30% or greater; reduced by about 40% or greater; reduced by about 50% or greater; and reduced by greater than about 75%.
  • Number of tumors may be measured by any reproducible means of measurement.
  • the number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification. In one aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x or 50x.
  • Treating cancer can result in a decrease in number of metastatic lesions in other tissues or organs distant from the primary tumor site.
  • the number of metastatic lesions is reduced by about 5% or greater relative to number prior to treatment; the number of metastatic lesions is reduced by about 10% or greater; reduced by about 20% or greater; reduced by about 30% or greater; reduced by about 40% or greater; reduced by about 50% or greater; and reduced by greater than about 75%.
  • the number of metastatic lesions may be measured by any reproducible means of measurement.
  • the number of metastatic lesions may be measured by counting metastatic lesions visible to the naked eye or at a specified magnification. In one aspect, the specified magnification is 2x, 3x, 4x, 5x, 10x, or 50x.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population receiving carrier alone.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; and by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; and by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in increase in average survival time of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof.
  • the average survival time is increased by more than 30 days; by more than 60 days; by more than 90 days; and by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving carrier alone. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. Treating cancer can result in a decrease in the mortality rate of a population of treated subjects in comparison to a population receiving monotherapy with a drug that is not a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof. In one aspect, the mortality rate is decreased by more than about 2%; by more than about 5%; by more than about 10%; and by more than about 25%. A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means.
  • a decrease in the mortality rate of a population may be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with an active compound.
  • a decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with an active compound.
  • Treating cancer can result in a decrease in tumor growth rate.
  • tumor growth rate is reduced by at least about 5% relative to number prior to treatment; tumor growth rate is reduced by at least about 10%; reduced by at least about 20%; reduced by at least about 30%; reduced by at least about 40%; reduced by at least about 50%; reduced by at least about 50%; and reduced by at least about 75%.
  • Tumor growth rate may be measured by any reproducible means of measurement. Tumor growth rate can be measured according to a change in tumor diameter per unit time.
  • Treating cancer can result in a decrease in tumor regrowth.
  • tumor regrowth is less than about 5%; tumor regrowth is less than about 10%; less than about 20%; less than about 30%; less than about 40%; less than about 50%; less than about 50%; and less than about 75%.
  • Tumor regrowth may be measured by any reproducible means of measurement. Tumor regrowth is measured, for example, by measuring an increase in the diameter of a tumor after a prior tumor shrinkage that followed treatment. A decrease in tumor regrowth is indicated by failure of tumors to reoccur after treatment has stopped.
  • Treating or preventing a cell proliferative disorder can result in a reduction in the rate of cellular proliferation.
  • the rate of cellular proliferation is reduced by at least about 5%; by at least about 10%; by at least about 20%; by at least about 30%; by at least about 40%; by at least about 50%; and by at least about 75%.
  • the rate of cellular proliferation may be measured by any reproducible means of measurement.
  • the rate of cellular proliferation is measured, for example, by measuring the number of dividing cells in a tissue sample per unit time.
  • Treating or preventing a cell proliferative disorder can result in a reduction in the proportion of proliferating cells.
  • the proportion of proliferating cells is reduced by at least about 5%; by at least about 10%; by at least about 20%; by at least about 30%; by at least about 40%; by at least about 50%; and by at least 75%.
  • the proportion of proliferating cells may be measured by any reproducible means of measurement.
  • the proportion of proliferating cells is measured, for example, by quantifying the number of dividing cells relative to the number of nondividing cells in a tissue sample.
  • the proportion of proliferating cells can be equivalent to the mitotic index.
  • Treating or preventing a cell proliferative disorder can result in a decrease in size of an area or zone of cellular proliferation.
  • size of an area or zone of cellular proliferation is reduced by at least about 5% relative to its size prior to treatment; reduced by at least about 10%; reduced by at least about 20%; reduced by at least about 30%; reduced by at least about 40%; reduced by at least about 50%; and reduced by at least about 75%.
  • Size of an area or zone of cellular proliferation may be measured by any reproducible means of measurement.
  • the size of an area or zone of cellular proliferation may be measured as a diameter or width of an area or zone of cellular proliferation.
  • Treating or preventing a cell proliferative disorder can result in a decrease in the number or proportion of cells having an abnormal appearance or morphology.
  • the number of cells having an abnormal morphology is reduced by at least about 5% relative to its size prior to treatment; reduced by at least about 10%; reduced by at least about 20%; reduced by at least about 30%; reduced by at least about 40%; reduced by at least about 50%; and reduced by at least about 75%.
  • An abnormal cellular appearance or morphology may be measured by any reproducible means of measurement.
  • An abnormal cellular morphology can be measured by microscopy, e.g., using an inverted tissue culture microscope.
  • An abnormal cellular morphology can take the form of nuclear pleiomorphism.
  • a compound of the invention acts selectively on a cancer or precancerous cell but not on a normal cell.
  • a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof acts selectively to modulate one molecular target (e.g., JAK3) but does not significantly modulate another molecular target (e.g., JAK2).
  • Compounds of the invention may also be used for selectively inhibiting or activating the activity of an enzyme, such as a kinase (e.g., JAK3).
  • an event occurs selectively in population A relative to population B if it occurs greater than two times more frequently in population A as compared to population B.
  • An event occurs selectively if it occurs greater than five times more frequently in population A.
  • An event occurs selectively if it occurs greater than ten times more frequently in population A; greater than fifty times; greater than 100 times; and greater than 1000 times more frequently in population A as compared to population B.
  • cell death would be said to occur selectively in cancer cells if it occurred greater than twice as frequently in cancer cells as compared to normal cells.
  • a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof can modulate the activity of a molecular target (e.g., JAK3). Modulating refers to stimulating or inhibiting an activity of a molecular target.
  • a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 10% relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • a compound of the invention modulates the activity of a molecular target if it stimulates or inhibits the activity of the molecular target by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 50-fold, at least 100-fold relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • the activity of a molecular target may be measured by any reproducible means.
  • the activity of a molecular target may be measured in vitro or in vivo.
  • the activity of a molecular target may be measured in vitro or in vivo by an enzymatic activity assay.
  • a compound of the invention does not significantly modulate the activity of a molecular target if the addition of the compound does not stimulate or inhibit the activity of the molecular target by greater than 10% relative to the activity of the molecular target under the same conditions but lacking only the presence of said compound.
  • isozyme selective means preferential inhibition or stimulation of a first isoform of an enzyme in comparison to a second isoform of an enzyme (e.g., preferential inhibition or stimulation of a kinase isozyme alpha in comparison to a kinase isozyme beta).
  • a change in enzymatic activity caused by a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof, can be measured in the disclosed assays.
  • the change in enzymatic activity can be characterized by the change in the extent of phosphorylation of certain substrates.
  • phosphorylation refers to the addition of phosphate groups to a substrate, including proteins and organic molecules; and, plays an important role in regulating the biological activities of proteins.
  • the phosphorylation assayed and measured involves the addition of phosphate groups to tyrosine residues.
  • the substrate can be a peptide or protein.
  • immunological reagents e.g., antibodies and antigens
  • Fluorescence can be utilized in the measurement of enzymatic activity in some assays.
  • fluorescence refers to a process through which a molecule emits a photon as a result of absorbing an incoming photon of higher energy by the same molecule. Specific methods for assessing the biological activity of a compound of the invention are described in the examples.
  • Activating refers to placing a composition of matter (e.g., protein or nucleic acid) in a state suitable for carrying out a desired biological function.
  • a composition of matter capable of being activated also has an unactivated state.
  • An activated composition of matter may have an inhibitory or stimulatory biological function, or both.
  • Elevation refers to an increase in a desired biological activity of a composition of matter (e.g., a protein or a nucleic acid). Elevation may occur through an increase in concentration of a composition of matter.
  • a composition of matter e.g., a protein or a nucleic acid
  • Treating cancer or a cell proliferative disorder can result in cell death, and cell death results in a decrease of at least about 10% in number of cells in a population.
  • cell death means a decrease of at least about 20%; a decrease of at least about 30%; a decrease of at least about 40%; a decrease of at least about 50%; a decrease of at least about 75%.
  • Number of cells in a population may be measured by any reproducible means. A number of cells in a population can be measured by fluorescence activated cell sorting (FACS), immunofluorescence microscopy and light microscopy. Methods of measuring cell death are as shown in Li et al., Proc Natl Acad Sci USA. 100(5): 2674-8, 2003 . In an aspect, cell death occurs by apoptosis.
  • an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof is not significantly cytotoxic to normal cells.
  • a therapeutically effective amount of a compound is not significantly cytotoxic to normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • a therapeutically effective amount of a compound does not significantly affect the viability of normal cells if administration of the compound in a therapeutically effective amount does not induce cell death in greater than 10% of normal cells.
  • cell death occurs by apoptosis.
  • Contacting a cell with a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof can induce or activate cell death selectively in cancer cells.
  • Administering to a subject in need thereof a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof can induce or activate cell death selectively in cancer cells.
  • Contacting a cell with a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof can induce cell death selectively in one or more cells affected by a cell proliferative disorder.
  • administering to a subject in need thereof a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof induces cell death selectively in one or more cells affected by a cell proliferative disorder.
  • Combination therapy includes the administration of a compound of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • Combination therapy is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Combination therapy also embraces the administration of the therapeutic agent(s) as described above in combination with other biologically active ingredients and/or non-drug therapies (e.g., surgery, immunotherapy or radiation treatment).
  • the combination therapy comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agent(s) and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof, may be administered in combination with a second anti-cancer agent.
  • the second anti-cancer agent (also referred to as an anti-neoplastic agent or anti-proliferative agent) can be an agent that modulates cancer metabolism, an alkylating agent; an antibiotic; an anti-metabolite; a detoxifying agent; an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a mitotic inhibitor; an MTOR inhibitor; a multi-kinase inhibitor; a serine/threonine kinase inhibitor; a tyrosine kinase inhibitors; a VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase inhibitor, an anthracycline, a microtubule targeting drug,
  • alkylating agents include, but are not limited to, cyclophosphamide (Cytoxan; Neosar); chlorambucil (Leukeran); melphalan (Alkeran); carmustine (BiCNU); busulfan (Busulfex); lomustine (CeeNU); dacarbazine (DTIC-Dome); oxaliplatin (Eloxatin); carmustine (Gliadel); ifosfamide (Ifex); mechlorethamine (Mustargen); busulfan (Myleran); carboplatin (Paraplatin); cisplatin (CDDP; Platinol); temozolomide (Temodar); thiotepa (Thioplex); bendamustine (Treanda); or streptozocin (Zanosar).
  • cyclophosphamide Cytoxan; Neosar
  • chlorambucil Leukeran
  • melphalan Alkeran
  • antibiotics include, but are not limited to, doxorubicin (Adriamycin); doxorubicin liposomal (Doxil); mitoxantrone (Novantrone); bleomycin (Blenoxane); daunorubicin (Cerubidine); daunorubicin liposomal (DaunoXome); dactinomycin (Cosmegen); epirubicin (Ellence); idarubicin (Idamycin); plicamycin (Mithracin); mitomycin (Mutamycin); pentostatin (Nipent); or valrubicin (Valstar).
  • doxorubicin Adriamycin
  • Doxil doxorubicin liposomal
  • mitoxantrone Novantrone
  • bleomycin Blenoxane
  • daunorubicin Cerubidine
  • daunorubicin liposomal DaunoXome
  • dactinomycin
  • Exemplary anti-metabolites include, but are not limited to, fluorouracil (Adrucil); capecitabine (Xeloda); hydroxyurea (Hydrea); mercaptopurine (Purinethol); pemetrexed (Alimta); fludarabine (Fludara); nelarabine (Arranon); cladribine (Cladribine Novaplus); clofarabine (Clolar); cytarabine (Cytosar-U); decitabine (Dacogen); cytarabine liposomal (DepoCyt); hydroxyurea (Droxia); pralatrexate (Folotyn); floxuridine (FUDR); gemcitabine (Gemzar); cladribine (Leustatin); fludarabine (Oforta); methotrexate (MTX; Rheumatrex); methotrexate (Trexall); thioguanine (Ta
  • Exemplary detoxifying agents include, but are not limited to, amifostine (Ethyol) or mesna (Mesnex).
  • interferons include, but are not limited to, interferon alfa-2b (Intron A) or interferon alfa-2a (Roferon-A).
  • Exemplary polyclonal or monoclonal antibodies include, but are not limited to, trastuzumab (Herceptin); ofatumumab (Arzerra); bevacizumab (Avastin); rituximab (Rituxan); cetuximab (Erbitux); panitumumab (Vectibix); tositumomab/iodine 131 tositumomab (Bexxar); alemtuzumab (Campath); ibritumomab (Zevalin; In-111; Y-90 Zevalin); gemtuzumab (Mylotarg); eculizumab (Soliris) ordenosumab.
  • Exemplary EGFR inhibitors include, but are not limited to, gefitinib (Iressa); lapatinib (Tykerb); cetuximab (Erbitux); erlotinib (Tarceva); panitumumab (Vectibix); PKI-166; canertinib (CI-1033); matuzumab (Emd7200) or EKB-569.
  • HER2 inhibitors include, but are not limited to, trastuzumab (Herceptin); lapatinib (Tykerb) or AC-480.
  • Histone Deacetylase Inhibitors include, but are not limited to, vorinostat (Zolinza).
  • hormones include, but are not limited to, tamoxifen (Soltamox; Nolvadex); raloxifene (Evista); megestrol (Megace); leuprolide (Lupron; Lupron Depot; Eligard; Viadur); fulvestrant (Faslodex); letrozole (Femara); triptorelin (Trelstar LA; Trelstar Depot); exemestane (Aromasin); goserelin (Zoladex); bicalutamide (Casodex); anastrozole (Arimidex); fluoxymesterone (Androxy; Halotestin); medroxyprogesterone (Provera; Depo-Provera); estramustine (Emcyt); flutamide (Eulexin); toremifene (Fareston); degarelix (Firmagon); nilutamide (Nilandron); abarelix (Pl
  • Exemplary mitotic inhibitors include, but are not limited to, paclitaxel (Taxol; Onxol; Abraxane); docetaxel (Taxotere); vincristine (Oncovin; Vincasar PFS); vinblastine (Velban); etoposide (Toposar; Etopophos; VePesid); teniposide (Vumon); ixabepilone (Ixempra); nocodazole; epothilone; vinorelbine (Navelbine); camptothecin (CPT); irinotecan (Camptosar); topotecan (Hycamtin); amsacrine or lamellarin D (LAM-D).
  • paclitaxel Taxol; Onxol; Abraxane
  • docetaxel Taxotere
  • vincristine Oncovin
  • Vincasar PFS vinblastine
  • Velban etop
  • Exemplary MTOR inhibitors include, but are not limited to, everolimus (Afinitor) or temsirolimus (Torisel); rapamune, ridaforolimus; or AP23573.
  • Exemplary multi-kinase inhibitors include, but are not limited to, sorafenib (Nexavar); sunitinib (Sutent); BIBW 2992; E7080; Zd6474; PKC-412; motesanib; or AP24534.
  • Exemplary serine/threonine kinase inhibitors include, but are not limited to, ruboxistaurin; eril/easudil hydrochloride; flavopiridol; seliciclib (CYC202; Roscovitrine); SNS-032 (BMS-387032); Pkc412; bryostatin; KAI-9803;SF1126; VX-680; Azd1152; Arry-142886 (AZD-6244); SCIO-469; GW681323; CC-401; CEP-1347 or PD 332991.
  • Exemplary tyrosine kinase inhibitors include, but are not limited to, erlotinib (Tarceva); gefitinib (Iressa); imatinib (Gleevec); sorafenib (Nexavar); sunitinib (Sutent); trastuzumab (Herceptin); bevacizumab (Avastin); rituximab (Rituxan); lapatinib (Tykerb); cetuximab (Erbitux); panitumumab (Vectibix); everolimus (Afinitor); alemtuzumab (Campath); gemtuzumab (Mylotarg); temsirolimus (Torisel); pazopanib (Votrient); dasatinib (Sprycel); nilotinib (Tasigna); vatalanib (Ptk787; ZK222584); CEP-701; SU5614
  • VEGF/VEGFR inhibitors include, but are not limited to, bevacizumab (Avastin); sorafenib (Nexavar); sunitinib (Sutent); ranibizumab; pegaptanib; or vandetinib.
  • microtubule targeting drugs include, but are not limited to, paclitaxel, docetaxel, vincristin, vinblastin, nocodazole, epothilones and navelbine.
  • topoisomerase poison drugs include, but are not limited to, teniposide, etoposide, adriamycin, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, epirubicin and idarubicin.
  • Exemplary taxanes or taxane derivatives include, but are not limited to, paclitaxel and docetaxol.
  • Exemplary general chemotherapeutic, anti-neoplastic, anti-proliferative agents include, but are not limited to, altretamine (Hexalen); isotretinoin (Accutane; Amnesteem; Claravis; Sotret); tretinoin (Vesanoid); azacitidine (Vidaza); bortezomib (Velcade) asparaginase (Elspar); levamisole (Ergamisol); mitotane (Lysodren); procarbazine (Matulane); pegaspargase (Oncaspar); denileukin diftitox (Ontak); porfimer (Photofrin); aldesleukin (Proleukin); lenalidomide (Revlimid); bexarotene (Targretin); thalidomide (Thalomid); temsirolimus (Torisel); arsenic trioxide (Trisenox);
  • the second chemotherapeutic agent can be a cytokine such as G-CSF (granulocyte colony stimulating factor).
  • a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, analog or derivative thereof may be administered in combination with radiation therapy. Radiation therapy can also be administered in combination with a compound of the invention and another chemotherapeutic agent described herein as part of a multiple agent therapy.
  • a compound of the invention may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and paclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP), Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molar ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Iri
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or solvate thereof may be administered with an inhibitor of an enzyme, such as a receptor or non-receptor kinase.
  • Receptor and non-receptor kinases of the invention are, for example, tyrosine kinases or serine/threonine kinases.
  • Kinase inhibitors of the invention are small molecules, polynucleic acids, polypeptides, or antibodies.
  • Exemplary kinase inhibitors include, but are not limited to, Bevacizumab (targets VEGF), BIBW 2992 (targets EGFR and Erb2), Cetuximab/Erbitux (targets Erb1), Imatinib/Gleevic (targets Bcr-Abl), Trastuzumab (targets Erb2), Gefitinib/Iressa (targets EGFR), Ranibizumab (targets VEGF), Pegaptanib (targets VEGF), Erlotinib/Tarceva (targets Erb1), Nilotinib (targets Bcr-Abl), Lapatinib (targets Erb1 and Erb2/Her2), GW-572016/lapatinib ditosylate (targets HER2/Erb2), Panitumumab/Vectibix (targets EGFR), Vandetinib (targets RET/VEGFR), E7080 (multiple
  • Exemplary serine/threonine kinase inhibitors include, but are not limited to, Rapamune (targets mTOR/FRAP1), Deforolimus (targets mTOR), Certican/Everolimus (targets mTOR/FRAP1), AP23573 (targets mTOR/FRAP1), Eril/Fasudil hydrochloride (targets RHO), Flavopiridol (targets CDK), Seliciclib/CYC202/Roscovitrine (targets CDK), SNS-032/BMS-387032 (targets CDK), Ruboxistaurin (targets PKC), Pkc412 (targets PKC), Bryostatin (targets PKC), KAI-9803 (targets PKC), SF1126 (targets PI3K), VX-680 (targets Aurora kinase), Azd1152 (targets Aurora kinase), Arry-142886/AZD-6244 (targets MAP/MEK
  • compositions are described as having, including, or comprising specific components, it is contemplated that compositions also consist essentially of, or consist of, the recited components.
  • processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps.
  • order of steps or order for performing certain actions are immaterial so long as the invention remains operable.
  • two or more steps or actions may be conducted simultaneously.
  • a compound of the invention or a pharmaceutically acceptable salt thereof is administered orally, nasally, transdermally, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally and parenterally.
  • a compound of the invention is administered orally.
  • the dosage regimen utilizing a compound of the invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • a compound of the invention or a pharmaceutically acceptable salt thereof is used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein.
  • a compound of the invention is prepared for oral administration, wherein a compound of the invention or a salt thereof is combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, pills, powders, syrups, solutions, suspensions and the like.
  • the tablets, pills, capsules, and the like contain from about 1 to about 99 weight percent of the active ingredient and a binder such as gum tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch or alginic acid; a lubricant such as magnesium stearate; and/or a sweetening agent such as sucrose, lactose, saccharin, xylitol, and the like.
  • a dosage unit form is a capsule, it often contains, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • various other materials are present as coatings or to modify the physical form of the dosage unit.
  • tablets are coated with shellac, sugar or both.
  • a syrup or elixir contains, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor, and the like.
  • a compound of the invention can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable compositions are aqueous isotonic solutions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, in another embodiment, the compositions contain about 1 to 50%, of the active ingredient.
  • injectable solutions are produced using solvents such as sesame or peanut oil or aqueous propylene glycol, as well as aqueous solutions of water-soluble pharmaceutically-acceptable salts of a compound of the invention.
  • solvents such as sesame or peanut oil or aqueous propylene glycol
  • aqueous solutions of water-soluble pharmaceutically-acceptable salts of a compound of the invention are prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions are, for example, topical preparations, suppositories or enemas.
  • Suppositories are advantageously prepared from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, in another embodiment, compositions contain about 1 to 50%, of the active ingredient.
  • a compound of the invention is formulated to deliver the active agent by pulmonary administration, e.g., administration of an aerosol formulation containing the active agent from, for example, a manual pump spray, nebulizer or pressurized metered-dose inhaler.
  • suitable formulations of this type also include other agents, such as antistatic agents, to maintain the compounds of the invention as effective aerosols.
  • a drug delivery device for delivering aerosols comprises a suitable aerosol canister with a metering valve containing a pharmaceutical aerosol formulation as described and an actuator housing adapted to hold the canister and allow for drug delivery.
  • the canister in the drug delivery device has a headspace representing greater than about 15% of the total volume of the canister.
  • the polymer intended for pulmonary administration is dissolved, suspended or emulsified in a mixture of a solvent, surfactant and propellant. The mixture is maintained under pressure in a canister that has been sealed with a metering valve.
  • a solid or a liquid carrier can be used for nasal administration.
  • the solid carrier includes a coarse powder having particle size in the range of, for example, from about 20 to about 500 microns and such formulation is administered by rapid inhalation through the nasal passages.
  • the formulation is administered as a nasal spray or drops and includes oil or aqueous solutions of the active ingredients.
  • formulations that are rapidly dispersing dosage forms also known as “flash dose” forms.
  • some embodiments of the present invention are formulated as compositions that release their active ingredients within a short period of time, e.g., typically less than about five minutes, in another embodiment, less than about ninety seconds, in another embodiment, less than about thirty seconds and in another embodiment, in less than about ten or fifteen seconds.
  • Such formulations are suitable for administration to a subject via a variety of routes, for example by insertion into a body cavity or application to a moist body surface or open wound.
  • a flash dosage is a solid dosage form that is administered orally, which rapidly disperses in the mouth, and hence does not require great effort in swallowing and allows the compound to be rapidly ingested or absorbed through the oral mucosal membranes.
  • suitable rapidly dispersing dosage forms are also used in other applications, including the treatment of wounds and other bodily insults and diseased states in which release of the medicament by externally supplied moisture is not possible.
  • Flash dose forms are known in the art; see for example, effervescent dosage forms and quick release coatings of insoluble microparticles in U.S. Pat. Nos. 5,578,322 and 5,607,697 ; freeze dried foams and liquids in U.S. Pat. Nos. 4,642,903 and 5,631,023 ; melt spinning of dosage forms in U.S. Pat. Nos. 4,855,326 , 5,380,473 and 5,518,730 ; solid, free-form fabrication in U.S. Pat. No. 6,471,992 ; saccharide-based carrier matrix and a liquid binder in U.S. Pat. Nos. 5,587,172 , 5,616,344 , 6,277,406 , and 5,622,719 ; and other forms known to the art.
  • a compound of the invention is also formulated as "pulsed release” formulations, in which the compound is released from the pharmaceutical compositions in a series of releases ( i.e., pulses).
  • a compound of the invention is also formulated as "sustained release” formulations in which the compound is continuously released from the pharmaceutical composition over a prolonged period.
  • formulations e.g., liquid formulations, including cyclic or acyclic encapsulating or solvating agents, e.g., cyclodextrins, polyethers, or polysaccharides (e.g., methylcellulose), or in another embodiment, polyanionic ⁇ -cyclodextrin derivatives with a sodium sulfonate salt group separate from the lipophilic cavity by an alkyl ether spacer group or polysaccharides.
  • the agent is methylcellulose.
  • the agent is a polyanionic ⁇ -cyclodextrin derivative with a sodium sulfonate salt separated from the lipophilic cavity by a butyl ether spacer group, e.g., CAPTISOL® (CyDex Pharmaceuticals Inc., Lenexa, KS).
  • a butyl ether spacer group e.g., CAPTISOL® (CyDex Pharmaceuticals Inc., Lenexa, KS).
  • suitable agent/compound formulation ratios by preparing a solution of the agent in water, e.g., a 40% by weight solution; preparing serial dilutions, e.g.
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50 °C for 2 hour and when completed sodium bicarbonate was added and the mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (150 mL). The milky mixture was heated to a boil and then left to cool to room temperature resulting in yellow crystals (1.4 g, 77% yield).
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 6-8 hours (conversion of starting materials was monitored by HPLC).
  • the solvent was removed under reduced pressure and the residue was taken in DCM and water.
  • the organic phase was collected and the product was extracted with plenty of DCM (due to poor solubility). The organic phase was evaporated yielding 3.4 g (69%) of green solid.
  • Triethylamine was added to a mixture of the acid and the activating agent in acetonitrile resulting in clear solution.
  • the components were stirred at room temperature and the active ester formation was monitored by HPLC. Then, pyrrolidine was added and immediate formation of the amide was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The solvent was then removed under reduced pressure, chloroform was added and the mixture was washed three times with saturated bicarbonate solution. The organic solvent was evaporated yielding a green powder (2 g, 73%).
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF (2:1). The reaction was stirred at 50°C for 2 h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1 h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • Reagent table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagent table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 3.15 g 10 bis(2,5-Dioxopyrrolidin-1-yl) carbonate 256.17 2.56 g 10 Acetonitrile-Dioxane 1:1 --- 200 mL --- Triethylamine 101 4.15 mL 22 Pyrrolidine 71.12 1.25 mL 15
  • Triethylamine was added to a mixture of the acid in in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC and small portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The solid was collected by filtration, washed with water (70 mL) and dried over vacuum (2 g, 73%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1 H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 2g 5.4 Pd/C --- 150 mg --- THF --- 50 mL ---
  • JAK3 JAK3 in 1% DMSO by several compounds was determined using the Z'-LYTE ® Biochemical Kinase Assay (Invitrogen, Madison, WI). The assays were performed according to manufacturer's protocols, except that prior to the kinase reaction they were pre-incubated for 2 hours at 4 °C, in order to be able to assay for time-dependent inhibition.
  • each 10 ⁇ L JAK3 kinase reaction contained 0.43 - 1.89 ng JAK3 and 2 ⁇ M peptide substrate in 50 mM HEPES (pH 7.5), 0.01% BRIJ-35, 10 mM MgCl 2 and 1 mM EGTA.
  • the kinase reaction was allowed to proceed for 1 hour.
  • the K i for the JAK3 activity cell free (2 hr preincubation at 4 °C) compounds of the invention is presented below in Table 1 (3 rd column).
  • the IC 50 for cell based JAK3 pathway inhibition for compounds of the invention is also presented below in Table 1 (4th column).
  • the IC 50 for cell based JAK3 pathway inhibition for compounds of the invention was determined as follows: STAT6-bla RA1 cells were thawed and resuspended in Assay Media (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 U/mL/100 ⁇ g/mL Pen/Strep, and 550 ng/mL CD40L) to a concentration of 781,250 cells/mL.
  • the compounds can be assessed against other tyrosine kinases and that the presentation of data is illustrative and in no way intended to limit the scope of the present invention.
  • the compounds of the invention can be assayed against a range of tyrosine kinases depending upon the performance activity desired to be gathered.
  • the letters "A”, “B”, “C”, “E”, “F”, “G”, and “H” are also illustrative and in no way is intended to limit the scope of the present invention.
  • the symbol “C” is not meant to indicate that a compound necessarily lacks activity or utility but rather that its K i value against the indicated tyrosine kinase is greater than 10 ⁇ M.
  • Example 2B B cell receptor NFAT-bla RA1 Inhibition Activity Assays
  • B cell receptor NFAT-bla RA1 activated by goat anti-human IgM, which stimulates the the SYK signaling pathway
  • the assays were performed according to manufacturer's protocols. See Example 3, Cell-line Specific Protocols B cell receptor activity in Ramos cells for details.
  • the IC 50 for B cell receptor NFAT-bla RA1 inhibition for compounds of the invention is presented below in Table 1 (6th column).
  • the data is presented whereby the letter “I” means the compound has an IC 50 between 0.0000001 ⁇ M ⁇ .1 ⁇ M, the letter “J” means the compound has an IC 50 between .11 ⁇ M ⁇ 1.0 ⁇ M, the letter “K” means the compound has an IC 50 between 1.1 ⁇ M ⁇ 10 ⁇ M, and the letter “L” means the compound has an IC 50 of >10 ⁇ M.
  • the letters "I”, “J”, “K”, and “L” are also illustrative and in no way is intended to limit the scope of the present invention.
  • Example 2C Interleukin 4/STAT6-STAT6-bla RA1 Inhibition Activity Assays
  • Interleukin 4/STAT6-STAT6-bla RA1 The inhibition of Interleukin 4/STAT6-STAT6-bla RA1 (activated by IL-4) by several compounds was determined using the Screening Protocol and Assay Conditions (Invitrogen, Madison, WI). The assays were performed according to manufacturer's protocols. Example 4, Cell-line Specific Protocols IL-4-stimulated STAT6 activity in Ramos cells for details. The IC 50 for Interleukin 4/STAT6-STAT6-bla RA1 inhibition for compounds of the invention is presented below in Table 1 (7th column).
  • This example describes assays for measuring the ability compounds of the invention to inhibit cell proliferation of a variety of cell lines and to inhibit several signal transduction pathways.
  • GeneBLAzer ® Technology uses a mammalian-optimized Beta-lactamase reporter gene ( bla ) combined with a FRET-enabled substrate to provide reliable and sensitive detection in intact cells.
  • Cells were loaded with an engineered fluorescent substrate containing two fluorophores, coumarin and fluorescein. Without bla expression, the substrate molecule remains intact. In this state, excitation of the coumarin results in fluorescence resonance energy transfer to the fluorescein moiety and emission of green light.
  • STAT6-bla RA1 cells were thawed. 32 ⁇ L of cell suspension were added to each well of a 384-well TC-Treated assay plate. Cells in Assay Media were incubated for 16-24 hours in the plate at 37°C/5% CO 2 in a humidified incubator. 4 ⁇ L of a 10X serial dilution of JAK Inhibitor I (control inhibitor starting concentration, 10,000 nM) or compound were added to appropriate wells of the plate and pre-incubated at 37°C/5% CO 2 in a humidified incubator with cells for 30 minutes. 4 ⁇ L of 10X control activator IL-4 at the predetermined EC 80 concentration was added to wells containing the control inhibitor or compound.
  • JAK Inhibitor I control inhibitor starting concentration, 10,000 nM
  • the plate was incubated for 5 hours at 37°C/5% CO 2 in a humidified incubator. 8 ⁇ L of 1 ⁇ M Substrate Loading Solution was added to each well and the plate was incubated for 2 hours at room temperature. The plate was read on a fluorescence plate reader.
  • NFAT-bla RA1 cells were thawed.
  • 4 ⁇ L of a 10X serial dilution of Syk Inhibitor II (control inhibitor starting concentration, 10,000 nM) or compound was added to appropriate wells of a Poly-D-Lysine assay plate.
  • 32 ⁇ L of cell suspension was added to the wells and pre-incubated at 37°C/5% CO 2 in a humidified incubator with compound and control inhibitor titration for 30 minutes.
  • 4 ⁇ L of 10X control activator Goat anti-Human IgM at the predetermined EC 80 concentration was added to wells containing the control inhibitor or compound.
  • the plate was incubated for 5 hours at 37°C/5% CO 2 in a humidified incubator.
  • 8 ⁇ L of 1 ⁇ M Substrate Loading Solution was added to each well and the plate was incubated for 2 hours at room temperature. The plate was read on a fluorescence plate reader.
  • Irf1-bla CTLL-2 cells were thawed and prepared as described above for the Activator Screen.
  • 32 ⁇ L of cell suspension was added to each well of a 384-well TC-Treated assay plate.
  • Cells in Assay Media were incubated for 16-24 hours in the plate at 37°C/5% CO2 in a humidified incubator.
  • 4 ⁇ L of a 10X serial dilution of JAK Inhibitor I (control inhibitor starting concentration, 1,000 nM) or compound was added to appropriate wells of the plate and pre-incubated at 37°C/5% CO2 in a humidified incubator with cells for 30 minutes.
  • 4 ⁇ L of 10X control activator EPO at the predetermined EC80 concentration was added to wells containing the control inhibitor or compound.
  • the plate was incubated for 5 hours at 37°C/5% CO2 in a humidified incubator. 8 ⁇ L of 1 ⁇ M Substrate Loading Solution was added to each well and the plate was incubated for 2 hours at room temperature. The plate was read on a fluorescence plate reader.
  • NFkB-bla THP-1 cells were thawed and resuspended in Assay Media (RPMI, 10% dialyzed FBS, 0.1 mM NEAA, 1mM Sodium Pyruvate, 100 U/mL/100 ⁇ g/mL Pen/Strep) to a concentration of 625,000 cells/mL. 32 ⁇ L of cell suspension (20,000 cells) were added to each well of a 384-well TC-Treated assay plate. Cells in Assay Media were incubated for 16-24 hours in the plate at 37°C/5% CO2 in a humidified incubator.
  • Assay Media RPMI, 10% dialyzed FBS, 0.1 mM NEAA, 1mM Sodium Pyruvate, 100 U/mL/100 ⁇ g/mL Pen/Strep
  • a solution was prepared of 5% DMSO solution (10x) in Assay Media.
  • a solution was prepared of 10X TNF ⁇ solution in Assay Medium. It is recoomended to run a dose response curve to determine the EC 80 for the Stimulation Solution.
  • This protocol is designed for loading cells with LiveBLAzerTM-FRET B/G Substrate (CCF4-AM) or CCF2-AM. If alternative substrates are used it is recommended to follow the loading protocol provided with the substrate. 6X LiveBLAzerTM-FRET B/G Substrate (CCF4-AM) or CCF2-AM Mixture was prepared and cell loading was done in the absence of direct strong lighting.
  • irf1-bla TF1 cells were thawed and resuspended in Assay Media (OPTI-MEM, 0.5% dialyzed FBS, 0.1 mM NEAA, 1mM Sodium Pyruvate, 100 U/mL/100 ⁇ g/mL Pen/Strep) to a concentration of 1,562,500 cells/mL. 32 ⁇ L of cell suspension (50,000 cells) were added to each well of a 384-well TC-Treated assay plate. Cells in Assay Media were incubated for 16-24 hours in the plate at 37°C/5% CO 2 in a humidified incubator.
  • Growth inhibitory activity against the human tumor cell lines, RS4;11 and Daudi was determined using Promega's Cell Titer-Glo ® assay.
  • the human tumor cells were placed in a 96-well microculture plate (Costar white, flat bottom # 3917) in a total volume of 90 ⁇ L/well. After 24 hours of incubation in a humidified incubator at 37 °C with 5% CO 2 and 95% air, 10 ⁇ L of serially diluted test agents in growth medium were added to each well. After 96 total hours of culture in a CO 2 incubator, the plated cells and Cell Titer-Glo ® (Promega # G7571) reagents were brought to room temperature to equilibrate for 30 minutes. 100 ⁇ L of Cell Titer-Glo ® reagent was added to each well. The plate was shaken for 2 minutes and then left to equilibrate for 10 minutes before reading luminescence on the Tecan GENios microplate reader.
  • Cell proliferation of the human B cell precursor leukemia tumor cell line NALM-6 was measured by a cell proliferation index assay.
  • This assay was based on the dilution rate of a fluorescent membrane marker which is directly linked to the cell division. Briefly, the assay was performed by loading the cells with a non-toxic fluorescent phospholipid analog before the seeding. The probe inserts stably into the plasmic membrane and was distributed between daughter cells after division. Flow cytometry analysis of the fluorescent probe was performed directly after the loading of the cells and after 96 hours of culture. The dilution rate of the fluorescent probe at the single cell level was directly correlated to the number of cell divisions. All experiments were performed in triplicate.
  • Detection of cellular events was performed in triplicate in 96 well-plates after 72 hours of treatment by automated flow cytometry. Non-linear regressions were performed with GraphPad Prism 4.01 sofware.
  • compounds of the invention are administered orally.
  • the pharmacological profile of compound 7A is shown below in Table 5. It meets the criteria for an oral clinical development candidate. Table 5.
  • Compounds of the invention are safe for administration.
  • excellent safety data was obtained in a 6-day maximum tolerated dose study at 100 mg/kg and 300 mg/kg of compound 7A, PO administered to six to eight-week old female ICR nude mice.
  • Animals administered compound 7 showed no mortality, no weight loss, no change in food consumption, no abnormalities in clinical observation, and necropsy was normal (internal and external).
  • Figure 1 shows changes in body weight for the study and Table 6 below shows individual food consumption in grams on day 1 and day 6 of the study. Table 6.
  • the anti-tumor effect of compounds of the invention can be evaluated in vivo.
  • the Daudi cell line culture was prepared using Daudi cell line (ATCC, USA), RPMI 1640 medium (Invitrogen, USA), and FBS (Invitrogen, Australia).
  • the female Balb/c nude mice (Slac Laboratory Animal Co., Ltd., Shanghai, China) were allowed a 3-day acclimatization period before the mice were implanted subcutaneously (s.c.) with 200 ⁇ l of 10 ⁇ 10 6 Daudi cells in 50% Matrigel in the right flank.
  • s.c. subcutaneously
  • the tumor-bearing mice were randomly assigned to groups of eight prior to dosing in 10 ml/kg of vehicle or compound 7A for 28 days.
  • the suspension of compound 7A was made fresh daily in 0.5% CMC (Sigma, USA) and 1% Tween 80 (Sigma, USA).
  • the difference between the mean values of tumor volume in treated and vehicle groups was analyzed for significance using one way ANOVA test at each time point after log transformation.
  • the difference between the mean values of tumor weight in treated and vehicle groups was analyzed for significance using t-test. In both analyses, P ⁇ 0.05 was considered to be statistically significant.
  • FIG. 2 is shows the changes in tumor volume.
  • Figures 3A and 3B compare tumor size and weight and Figure 3C compares changes in body weight.
  • CIA mouse collagen induced arthritis
  • the CIA studies utilized a mild (slow-progressing) disease model.
  • the DBA/1 mice developed collagen induced arthritis (CIA) after immunization with Hooke KitTM chicken collagen /Complete Freund's Adjuvant (CFA) emulsion (EK-0210), followed by a booster dose of Hooke KitTM chicken collagen / Incomplete Freund's Adjuvant (IFA) emulsion (EK-0211).
  • CFA Complete Freund's Adjuvant
  • IFA Incomplete Freund's Adjuvant
  • Each study used 54 female DBA/1 mice (Taconic Farms model DBA1BO, 9 weeks old) later assigned to 4 experimental groups with 10 mice per group. 4 mice were not immunized nor treated, and they were left as naive controls group for possible histological analysis. The other 50 mice were treated therapeutically.
  • One study comprises group 1 - Vehicle, group 2 - CP-690550, 30mg/kg PO QD, group 3 - R-788, 60 mg/kg PO QD and group 4 - compound 7, 100 mg/kg, IP QD.
  • the other study comprises group 1 - Vehicle, group 2 - compound 7, 15mg/kg PO QD, group 3-compound 7, 30 mg/kg PO QD and group 4 - compound 7, 100 mg/kg, IP QD.
  • mice were first immunized with collagen/CFA emulsion on Day 0 after being acclimated for at least 7 days.
  • the procedure of immunization was as follows: A mouse was immobilized using a restrainer. The tail was cleaned with 70% ethanol and the area was wiped dry with sterile gauze. The syringe containing collagen/CFA emulsion was positioned parallel to the tail and the tip of the needle was pointed toward the body of the mouse, over the space between the dorsal and lateral vein of the tail. The needle was inserted 7 to 10 mm into the subcutaneous space to ensure the needle visible under the skin. The site of needle entry was pressed firmly to prevent any back-leakage of emulsion during the injection.
  • mice 0.05 ml of the emulsion was injected as the white emulsion was seen entering the subcutaneous space.
  • the needle was kept inserted for 10 to 15 seconds after the injection to avoid leakage of the emulsion. Then the mouse was released back to the cage. The procedure was repeated with all the mice.
  • the procedure of booster with chicken collagen/IFA on Day 21 was as follows: An immunized mouse was immobilized using a restrainer. The tail was cleaned with 70% ethanol and the area was wiped dry with sterile gauze. The syringe/needle containing type II collagen/IFA emulsion was positioned parallel to the tail and the tip of the needle was pointed toward the body of the mouse. The emulsion was injected at the side of the tail which had not received the initial immunization injection. And the pale area was chosen for injection to avoid puncturing a dilated blood vessel or its close area. The needle was inserted 7 to 10 mm into the subcutaneous space to ensure the needle visible under the skin.
  • the needle and the tail were pressed very tightly at the site of needle entry to prevent any back-leakage of emulsion during the injection.
  • 0.05 ml of the emulsion (or 0.025 ml of emulsion at two sites) was injected very slowly.
  • the needle was kept inserted for 10 to 15 seconds after the injection to avoid leakage of the emulsion.
  • the mouse was released back to the cage. The procedure was repeated with all the immunized mice.
  • mice were checked for signs of CIA every 2 to 3 days, starting on day 14 after the immunization. As soon as the first signs of joint inflammation occur, the mice were provided with food pellets and wet food on the floor of the cage, and easily accessible water. Transgel (Charles River Laboratories) was used as a source of water.
  • mice were initially considered a single group until booster with chicken collagen/IFA on Day 21. Mice with any signs of arthritis on Day 21 were excluded from the study. Each mouse with newly developed clinical signs of CIA was assigned to 1 of the 5 experimental groups in a balanced manner and treatment of those mice was initiated on the same day.
  • mice were orally dosed at the same time every day (+/- 1 hour) until the end of the study.
  • the compounds of the invention were formulated weekly (3 preparations in total).
  • CIA scores Daily CIA scoring started on Day 21 and continued until 40 mice were enrolled into the study. After enrollment, mice were scored every other day. CIA scoring was performed blind, by a person unaware of both treatment and of previous scores for each mouse. Mice were scored on the scale of 0 to 16 (0 to 4 for each paw, adding the scores for all 4 paws), using the following criteria: Paw Score Clinical Observations 0 Normal paw. 1 One toe inflamed and swollen. 2 More than one toe, but not entire paw, inflamed and swollen, OR Mild swelling of entire paw. 3 Entire paw inflamed and swollen. 4 Very inflamed and swollen paw or ankylosed paw. If the paw is ankylosed, the mouse cannot grip the wire top of the cage.
  • Ankylosis scores Ankylosis scoring was performed blind, by a person unaware of both treatment and of previous scores for each mouse. At the same time CIA scoring was performed (both during and after enrollment), ankylosis was scored as the sum of scores from 0-3 for each paw using the following criteria: Paw Score Clinical Observations 0 No ankylosis 1 Mild ankylosis 2 Moderate ankylosis 3 Severe ankylosis
  • Body weight was measured on Day -1 (one day before immunization) and then again on the day of enrollment. After enrollment, body weight was measured every other day.
  • Hind paw thickness Twice between Days 1 and 14 after immunization (before enrollment begins), both hind paws of all the mice were measured using calipers to establish baseline values for paw thickness.
  • each mouse was examined for hind paw swelling. Those mice with a swollen hind paw at that time had that paw measured with calipers. If both hind paws were swollen, the more swollen paw was measured.Those mice thereafter had the same hind paw measured with calipers at the same time as CIA scoring. Mice which first developed paw swelling in a front paw did not have thickness of any of their paws measured after enrollment.
  • Figures 4A and 4B show the results of positive controls in mild disease models.
  • the control compounds are CP-690,550 (tofacitinib), a pan-JAK inhibitor in Phase III clinical trials for Pfizer and R-788 (fostamatinib), a non-selective SYK inhibitor in Phase III clinical trials for Rigel/AstraZeneca.
  • Figure 4A shows the CIA score over 20 treatment days with the positive controls in the known mild disease model.
  • CP-690,550 was administered at 30mg/kg PO QD and R-788 was administered at 60 mg/kg PO QD.
  • Figure 4B shows the disease severity score for 20 days post treatment with positive controls in the known semi-therapeutic CIA model (Pfizer 2010)(H.T.
  • FIG. 4C shows the results of compound 7A in the mild CIA model in comparison to controls.
  • Compound 7A showed a reduction in CIA score on the last day vs. combined vehicle ( Figure 4D ).
  • An increase in hind paw thickness is a sign of arthritis.
  • Figures 4E and 4F show the results of hind paw thickness following treatment over 20 days administering compound 7A at 100 mg/kg IP QD in comparison to positive controls.
  • Figure 4G shows CIA scores for compound 7A administered at 3 different dosage amounts (15mg/kg PO QD, 30 mg/kg PO QD, and 100 mg/kg IP QD) over 20 days.
  • Reagents table Synthesis of 2 Reagent raw/ material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (Quantitative, yellow powder).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 4-(2-(phenylamino)thiazol-4-yl)-1 H-pyrrole-2-carboxylate 299 5.98 g 20 NaOH 40 3.2 g 80 Dioxane --- 100 mL --- H 2 O --- 50 mL ---
  • Triethylamine was added to a mixture of the acid in acetonitrile resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC and small portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The organic solvent was removed under reduced pressure. DCM was added along with saturated bicarbonate solution. The precipitate formed upon shaking in the separatory funnel was collected by filtration and washed with boiling MeOH. (1.3 g, 38%). HPLC - 98% purity. LCMS - (ES + ) Calcd. 338.43, found 339.25 (MH + ).
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table - Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 3.15 g 10 bis(2,5-Dioxopyrrolidin-1-yl) carbonate 256.17 2.56 g 10 Acetonitrile - 200 mL - Triethylamine 101 4.15 mL 22 pyrrolidine 71.12 1.25 mL 15
  • Triethylamine was added to a mixture of the acid in in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC and small portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The Organic solvent was removed under reduced pressure.
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 4 Reagents/raw material MW (gr/mole) Quantity mmoles Methyl 4-(2-(3-nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylate 329.33 6.6 g 20 NaOH 40 3.2 g 80 Dioxane --- 100 mL --- H 2 O --- 50 mL ---
  • Triethylamine was added to a mixture of the acid in in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC and small portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The Organic solvent was removed under reduced pressure.
  • Reagents table Synthesis of 2 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Triethylamine was added to a mixture of the acid and activating agent in acetonitrile. No solubility was observed, dioxane was added resulting in clear solution. Active ester formation was monitored by HPLC and small portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were added until full conversion of the active ester was observed. The organic solvent was removed under reduced pressure. Ethyl acetate was added along with saturated bicarbonate solution. The precipitate formed upon shaking in the separatory funnel was collected by filtration.
  • Reagents table Synthesis of 2 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 2 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 2 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlC 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 2 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagent table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 1125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Triethylamine was added to a mixture of the acid in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water (70 mL) and dried over vacuum (2 g, 73%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 2 g 5.4 Pd/C --- 150 mg --- THF --- 50 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Triethylamine was added to a mixture of the acid in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water (70 mL) and dried over vacuum (2 g, 73%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 2 g 5.4 Pd/C --- 150 mg --- THF --- 50 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 4-Nitrobrhioenzamide 182 2.00 g 11 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 2.22 g 11 Sodium acetate 82 1.80 g 22 Acetic acid --- 8 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (2.86 g 79% mustard yellow powder).
  • Triethylamine was added to a mixture of the acid in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added (1.28 g, 5 mmole total) until a point of 95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water (100 mL) and dried over vacuum (1.6 g, 50%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 1.6 g 4.3 Pd/C --- 150 mg --- THF --- 300 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 630.6 mg 2.0 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 769 mg 3.0 Acetonitrile-Dioxane 1:1 --- 40 mL --- Triethylamine 101 0.84 mL 6.0 Dimethylamine 45.1 3 mL 5.0
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, dimethylamine was added and an immediate formation of the amide was observed (the color of the reaction changed). Additional portions of dimethylamine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, washed with water and dried under high vacuum to afford the desired product as a brownish solid: 580 mg, 84.7 % yield.
  • the nitro compound was dissolved in boiling THF.
  • the catalyst was added and the mixture was subjected to hydrogen atmosphere for 48 h.
  • the catalyst was removed by filtration over celite and the solvent was evaporated yielding the product as a yellow solid: 470 mg, 89 % yield.
  • Reagents table - Synthesis of 7 and 8 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Aminophenyl)thiazol-4-yl)-N,N-dimethyl-1 H-pyrrole-2-carboxamide 312.4 470 mg 1.5 Chloroacetylchloride 113 0.13 mL 1.65 Triethylamine 101 0.63 mL 4.5 Morpholine 87.12 0.12 mL 1.5 Triethylamine* 101 0.21 mL 1.5 DCM --- 25mL --- Dioxane --- 8 mL --- * Synthesis of 8
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 630.6 mg 2.0 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 769 mg 3.0 Acetonitrile-Dioxane 1:1 --- 40 mL --- Triethylamine 101 0.84 mL 6.0 Dimethylamine 45.1 3 mL 5.0
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, dimethylamine was added and an immediate formation of the amide was observed (the color of the reaction changed). Additional portions of dimethylamine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, washed with water and dried under high vacuum to afford the desired product as a brownish solid: 580 mg, 84.7 % yield.
  • the nitro compound was dissolved in boiling THF.
  • the catalyst was added and the mixture was subjected to hydrogen atmosphere for 48 h.
  • the catalyst was removed by filtration over celite and the solvent was evaporated yielding the product as a yellow solid: 470 mg, 89 % yield.
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 630.6 mg 2.0 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 769 mg 3.0 Acetonitrile-Dioxane 1:1 --- 40 mL --- Triethylamine 101 0.84 mL 6.0 Dimethylamine 45.1 3 mL 5.0
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, dimethylamine was added and an immediate formation of the amide was observed (the color of the reaction changed). Additional portions of dimethylamine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, washed with water and dried under high vacuum to afford the desired product as a brownish solid: 580 mg, 84.7 % yield.
  • the nitro compound was dissolved in boiling THF.
  • the catalyst was added and the mixture was subjected to hydrogen atmosphere for 48 h.
  • the catalyst was removed by filtration over celite and the solvent was evaporated yielding the product as a yellow solid: 470 mg, 89 % yield.
  • Reagents table - Synthesis of 7 and 8 Reagent/raw material MW (gr/ mole) Quantity mmoles 4-(2-(3-Aminophenyl)thiazol-4-yl)-N,N-dimethyl-1H-pyrrole-2-carboxamide 312.4 470 mg 1.5 Chloroacetylchloride 113 0.13 mL 1.65 Triethylamine 101 0.63 mL 4.5 1-Methylpiperazine 100.2 150.3 mg 1.5 Triethylamine* 101 0.21 mL 1.5 DCM --- 25mL --- Dioxane --- 8 mL --- * Synthesis of 8
  • Reagents table - Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL -
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1 h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Triethylamine was added to a mixture of the acid in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water (70 mL) and dried over vacuum (2 g, 73%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-y)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 2g 5.4 Pd/C --- 150 mg --- THF --- 50 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1 h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 0.945 g 3 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 0.768+0.384 g 3+1.5 Acetonitrile-Dioxane 1:1 --- 50 mL --- Triethylamine 101 1.25 mL 9 Cyclopropylamine 57.1 0.7 mL 10
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, cyclopropylamine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, and the filtrate (90% purity) was evaporated and the resulting solid was stirred in water (30 mL). Vacuum drying afforded 0.46 g (43%) of yellow solid.
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Triethylamine was added to a mixture of the acid in acetonitrile-dioxane mixture resulting in clear solution.
  • the activating agent was then added and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water (70 mL) and dried over vacuum (2 g, 73%).
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.41 2 g 5.4 Pd/C --- 150 mg --- THF --- 50 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 0.790 g 2.5 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 0.64g+0.32g 2.5+1.25 Acetonitrile-Dioxane 1:1 --- 50 mL --- Triethylamine 101 1.04 mL 7.5 Ammonia in MeOH (7M) 57.1 0.7 mL 10
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 95% conversion. Then, ammonia solution was added and an immediate formation of the amide (precipitate) was observed. Additional portions of ammonia were introduced until full conversion of the active ester was observed. The solid obtained was collected by filtration, washed with water, taken in EtOH and evaporated to dryness yielding 0.32 g (1.02 mmole, 40% yield) of yellow powder.
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1 h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • Reagents table Synthesis of 3 Reagent/raw material MW (gr/mole) Quantity mmoles 3-Nitrobrhioenzamide 182 4.55 g 25 Methyl 4-(2-chloroacetyl)-1H-pyrrole-2-carboxylate 201.6 5.04 g 25 Sodium acetate 82 4.1 g 50 Acetic acid --- 20 mL ---
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 0.780 g 2.5 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 0.64g+0.32g 2.5+1.25 Acetonitrile-Dioxane 1:1 --- 30 mL --- Triethylamine 101 1.04 mL 7.5 Diethylamine 73.14 0.82 mL 8
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 97% conversion. Then, diethylamine was added. Additional portions of diethylamine were introduced until full conversion of the active ester was observed. The solvents were removed under reduced pressure. DCM was added and the solution was washed with saturated sodium bicarbonate solution. The organic phase was dried over Na 2 SO 4 and evaporated yielding 0.8g (86%) of yellow powder.
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles N,N-Diethyl-4-(2-(3-nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxamide 370.43 0.80 g 2.2 Pd/C --- 120 mg --- THF --- 150 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Lawesson's reagent was added to a stirring mixture of 3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (2.8 g, 77% yield).
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 3-5 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (90% mustard yellow powder).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 315.3 0.78 g 2.5 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 0.64+0.32 g 2.5 Acetonitrile-Dioxane 1:1 --- 50 mL --- Triethylamine 101 1.03 mL 7.5 Piperidine 85.15 0.98 mL 10
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, piperidine was added and an immediate formation of the amide (precipitate) was observed. Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, and the filtrate (90% purity) was evaporated and the resulting solid was stirred in water (30 mL). Vacuum drying afforded 0.33 g (34%) of yellow solid.
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(piperidin-1-yl)methanone 382.43 0.33 g 0.86 Pd/C --- 100 mg --- THF --- 150 mL ---
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---
  • Lawesson's reagent was added to a stirring mixture of 4-methoxy-3-nitrobenzamide in dimethoxyethane-THF 2:1. The reaction was stirred at 50°C for 2h and when completed sodium bicarbonate was added and the mixture was stirred at rt for 1h. The solvents were removed under reduced pressure and the oily residue was slowly added to a stirring mixture of water and crushed ice (300 mL). The milky mixture was heated to boil and then left to cool to rt. resulting in yellow crystals. (0.9 g, 76 % yield).
  • the reagents were stirred in acetic acid and heated to reflux resulting in a clear solution followed by precipitation formation.
  • the mixture was refluxed for 2 hours (conversion of starting materials was monitored by HPLC).
  • the mixture was cooled to rt, and the solid was collected by filtration, washed with ice water (80 mL), air dried and then vacuum dried. (1.04 g, 68 % orange solid).
  • Reagents table Synthesis of 5 Reagent/raw material MW (gr/mole) Quantity mmoles 4-(2-(4-Methoxy-3-nitrophenyl)thiazol-4-yl)-1H-pyrrole-2-carboxylic acid 345.3 980 mg 2.8 bis(2,5-Dioxopyrrolidin-1-yl) carbonate (DSC) 256.17 1.09 g 4.2 Acetonitrile-Dioxane 1:1 --- 60 mL --- Triethylamine 101 1.2 mL 8.5 Pyrrolidine 71.1 0.6 mL 7.1
  • DSC was added to a solution of the acid and triethylamine in dioxane-acetonitrile and the components were stirred at rt. Active ester formation was monitored by HPLC. Extra portions of the activating agent were added until a point of 90-95% conversion. Then, pyrrolidine was added and an immediate formation of the amide was observed (the color of the reaction changed). Additional portions of pyrrolidine were introduced until full conversion of the active ester was observed. The solid obtained was removed by filtration, washed with water and dried under high vacuum to afford the desired product as an orange solid: 1.04 g, 91.9 % yield.
  • Reagents table Synthesis of 6 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(4-Methoxy-3-nitrophenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 398.4 1.04 g 2.61 Pd/C --- 150 mg cat. THF --- 100 mL ---
  • the nitro compound was dissolved in boiling THF.
  • the catalyst was added and the mixture was subjected to hydrogen atmosphere for 48 h.
  • the catalyst was removed by filtration over celite and the solvent was evaporated yielding the product as a yellow solid: 950 mg, 98.8 % yield.
  • Reagents table - Synthesis of 7 and 8 Reagent/raw material MW (gr/mole) Quantity mmoles (4-(2-(3-Amino-4-methoxyphenyl)thiazol-4-yl)-1H-pyrrol-2-yl)(pyrrolidin-1-yl)methanone 368.5 950 mg 2.6 Chloroacetylchloride 113 0.23 mL 2.8 Triethylamine 101 1.09 mL 7.7 Morpholine 87.1 0.17 mL 1.94 Triethylamine* 101 0.27 mL 1.94 DCM --- 40 mL --- Dioxane --- 12 mL --- * Synthesis of 8
  • Reagents table Synthesis of 1 Reagent/raw material MW (gr/mole) Quantity mmoles Methyl 1H-pyrrole-2-carboxylate 125.13 6.25 g 50 AlCl 3 133.34 16.67 g 125 Chloroacetyl chloride 113 10 mL 125 DCM --- 100 mL ---

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US4642903A (en) 1985-03-26 1987-02-17 R. P. Scherer Corporation Freeze-dried foam dosage form
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US4855326A (en) 1987-04-20 1989-08-08 Fuisz Pharmaceutical Ltd. Rapidly dissoluble medicinal dosage unit and method of manufacture
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US5578322A (en) 1990-11-30 1996-11-26 Yamanouchi Pharmaceutical Co., Ltd. Quick release coated preparation
US5518730A (en) 1992-06-03 1996-05-21 Fuisz Technologies Ltd. Biodegradable controlled release flash flow melt-spun delivery system
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US5622719A (en) 1993-09-10 1997-04-22 Fuisz Technologies Ltd. Process and apparatus for making rapidly dissolving dosage units and product therefrom
US5607697A (en) 1995-06-07 1997-03-04 Cima Labs, Incorporated Taste masking microparticles for oral dosage forms
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US6277406B1 (en) 1997-10-08 2001-08-21 Fuisz Technologies Ltd. Easily processed tablet compositions
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